Abuse-deterrent dosage forms containing esketamine

ABSTRACT

Disclosed herein are immediate release oral dosage forms that contain abuse-deterrent and abuse-resistant features. In particular, the disclosed dosage forms can provide deterrence of abuse by ingestion of multiple individual doses. The disclosed dosage forms can likewise provide protection from overdose in the event of accidental or intentional ingestion of multiple individual doses. The dosage forms may also exhibit abuse resistant properties when physically manipulated, and also when physically manipulated and then administered in a manner not consistent with oral dosing. The dosage forms may also exhibit abuse resistant properties when administered in a manner intended to result in administration of the esketamine in a higher than therapeutic dose.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. Application No.17/523,193, filed Nov. 10, 2021, which is a continuation-in-part of U.S.Pat. App. No. 16/869,309, filed May 7, 2020, issued as U.S. Pat. No.11,324,707 on May 10, 2022, which claims the benefit of priority to U.S.Provisional App. No. 62/844,286, filed May 7, 2019, the entire contentsof which are hereby incorporated by reference.

TECHNICAL FIELD

The present disclosure pertains to oral dosage forms that containabuse-deterrent features.

BACKGROUND

Pharmaceutical products, including both prescription andover-the-counter pharmaceutical products, while useful for improvinghealth or alleviating undesirable symptoms of a person in need, are alsosusceptible to intentional and unintentional abuse and overdosing.Commonly abused active pharmaceutical ingredients include psychoactivedrugs, anxiolytics, sedative hypnotics, stimulants, depressants, andanalgesics such as narcotic analgesics, among others.

Some common techniques for intentionally abusing a drug may begin with aprospective abuser obtaining a solid dosage form, such as an orallyadministered tablet or capsule, and crushing the solid dosage form intoa powder. The powder may be administered by an abuser by nasalinsufflation to introduce the drug to the abuser’s bloodstreamintranasally. Alternately, the crushed dosage form may be combined witha solvent that is capable of dissolving the drug (active pharmaceuticalingredient, or “API”) and the solvent containing the dissolved drug maythen be injected directly into an abuser’s bloodstream. In the case ofimmediate release oral dosage forms, an abuser might simply ingestmultiple units (e.g., tablets) of the dosage form together, e.g.,simultaneously, or over an abbreviated period of time. Each one of themultiple dosage form units immediately releases an amount of drug,thereby producing a short-term concentration spike of the drug in theuser’s bloodstream and the desired “high” in the user.

The pharmaceutical industry has identified various mechanisms ofadapting drug compositions and oral dosage forms to discourage abuse oforal dosage forms. Pharmaceutical companies have studied dosage formsthat contain a nasal irritant or an effervescent agent, which can causeirritation or pain in a nasal passage if the dosage form is crushed andthen snorted, thus discouraging abuse by nasal insufflation.

Pharmaceutical companies studied adding gelling polymers to dosage formsto prevent abuse by injection. If the dosage form is crushed to a powderand combined with a small amount of solvent, the gelling polymer cancause the combination to take the form of a highly viscous liquid or gelthat cannot be administered by injection. Another possible abusedeterrent may be addition of an emetic agent which can deter abuse bycausing emesis on ingestion of multiple doses. Another abuse deterrentinvolves adding an antagonist of an API to a dosage form that willsubstantially block the effect of the drug.

Although the pharmaceutical industry has identified of a variety ofabuse deterrent (sometimes referred to as “abuse-resistant”) featuresuseful with oral dosage forms, there is continuing need to improve abusedeterrent features in order to prevent abuse or overdosing of activepharmaceutical ingredients.

SUMMARY

Disclosed herein are oral dosage forms comprising: (i) a firstpopulation of core-shell particles, each of the core-shell particles ofthe first population comprising a core that includes a gelling polymerand a wax; an active pharmaceutical layer surrounding the core, theactive pharmaceutical layer comprising esketamine; and at least onelayer surrounding the active pharmaceutical layer, the at least onelayer comprising a pH-sensitive film comprising a pH-sensitive polymerthat is insoluble in water at a pH greater than 5; and, (ii) a matrixcomprising a carbomer gelling polymer and sodium bicarbonate, whereinthe carbomer gelling polymer and sodium bicarbonate are present in saiddosage form in a ratio by weight percentage of about 2:2 based on thetotal weight of the dosage form; wherein the dosage form exhibits animmediate release profile of the esketamine when administered to a humanin therapeutic doses, and an extended release profile of the esketaminewhen administered to a human in supratherapeutic doses.

Also disclosed herein are abuse resistant oral dosage forms for theadministration of esketamine to a subject comprising: (i) a firstpopulation of core-shell particles, each of the core-shell particles ofthe first population comprising a core, an active pharmaceutical layersurrounding the core comprising esketamine or a pharmaceuticallyacceptable salt thereof, and at least one layer surrounding the activepharmaceutical layer, the at least one layer comprising a pH-sensitivefilm comprising a pH-sensitive polymer that is insoluble in water at apH greater than 5; and, (ii) a matrix comprising a carbomer gellingpolymer and sodium bicarbonate, wherein the carbomer gelling polymer andsodium bicarbonate are present in a ratio by weight percentage of about2:2 based on the total weight of the dosage form; wherein the dosageform exhibits an immediate release profile of esketamine having not lessthan 90% of the esketamine released in 60 minutes, wherein the releaseprofile is evaluated by dissolution of the tablet in 300 mL of 0.1N HC1media using USP II apparatus at 50 RPM paddle speed and 37° C.; whereinthe dosage form exhibits an immediate release profile of the esketaminewhen administered to a human in therapeutic doses, and an extendedrelease profile of the esketamine when administered to a human insupratherapeutic doses,, or wherein the dosage form exhibits abuseresistant properties when physically manipulated, or wherein the dosageform exhibits abuse resistant properties when physically manipulated andadministered in a manner not consistent with oral dosing, or wherein thedosage form exhibits abuse resistant properties when administered in amanner intended to result in administration of the esketamine in ahigher than therapeutic dose.

The present disclosure also provides oral tablets for the administrationof esketamine to a subject comprising: a total weight of not less than800 mg, and having 40 mg of esketamine (base equivalent), the esketamine(base equivalent) representing less than 5.0% by weight of the totalweight of the tablet, or a total weight of not less than 571 mg, andhaving 20 mg of esketamine (base equivalent), the esketamine (baseequivalent) representing less than 3.5% by weight of the total weight ofthe tablet; wherein the tablet exhibits an immediate release profile ofesketamine having not less than 90% of the esketamine released in 60minutes, and wherein the release profile is evaluated by dissolution ofthe tablet in 300 mL of 0.1N HC1 media using USP II apparatus at 50 RPMpaddle speed and 37° C.; and wherein the dosage form exhibits animmediate release profile of the esketamine when administered to a humanin therapeutic doses, and an extended release profile of the esketaminewhen administered to a human in supratherapeutic doses, or wherein thetablet exhibits abuse resistant properties when physically manipulated,or wherein the tablet exhibits abuse resistant properties whenphysically manipulated and administered in a manner not consistent withoral dosing, or wherein the tablet exhibits abuse resistant propertieswhen administered in a manner intended to result in administration ofthe esketamine in a higher than therapeutic dose.

Also disclosed are methods of reducing the potential for abuse by ahuman of an active pharmaceutical ingredient comprising esketamine,comprising providing to the human a dosage form as described herein.

Also provided are methods of reducing the potential for abuse by a humanof an active pharmaceutical ingredient comprising esketamine bysimultaneous oral ingestion of multiple dosage units comprising theactive pharmaceutical ingredient, comprising providing to the human adosage form as described herein.

The present disclosure also provides methods for treating or preventingpain or discomfort in a subject in need thereof by administering to thesubject a dosage form as described herein.

Also disclosed are methods for treating depression in a subject in needthereof by administering to the subject a dosage form as describedherein.

The present disclosure also provides methods of reducing the potentialfor abuse by nasal insufflation by a human of an active pharmaceuticalingredient comprising esketamine, comprising providing to the human adosage form as described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A, FIG. 1B, and FIG. 1C illustrate embodiments of core-shellparticles, in cross section, for inclusion in the presently discloseddosage forms.

FIG. 2A and FIG. 2B also illustrate embodiments of core-shell particles,in cross section.

FIG. 3 is a perspective view of an embodiment of a dosage form asdisclosed herein.

FIG. 4 shows the results of single-tablet dissolution testing of aninventive dosage form according to the present disclosure and of acomparative dosage form.

FIG. 5 shows the results of multiple-tablet dissolution testing of asupratherapeutic dose of an inventive dosage form according to thepresent disclosure and of a supratherapeutic dose of comparative dosageform.

FIG. 6 provides an image of a dual screen apparatus that was used totest a supratherapeutic dose of an inventive dosage form with gelretained on the screens.

FIG. 7 provides an image of a dual screen apparatus that was used totest a supratherapeutic dose of a comparative dosage form with gelretained on the screens.

FIG. 8 provides an image of a dual screen apparatus that was used totest a supratherapeutic dose of a comparative dosage form with gelretained on the screens.

FIG. 9 provides an image of a gel resulting from a supratherapeutic doseof inventive dosage forms, suspended in a test medium.

FIG. 10 provides an image of a gel resulting from a supratherapeuticdose of comparative dosage forms, suspended in a test medium.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Abuse deterrent and resistant features can include the ability of adosage form to produce a highly viscous liquid or gel when crushed andexposed to a solvent, when administered in supratherapeutic doses (indoses that are higher than what is prescribed pursuant to a legitimatetreatment regimen), or both, in order to prevent abuse by such methodsas intravenous injection, nasal insufflation, and oral supratherapeuticdosing. One challenge associated with incorporating this type ofabuse-deterrent feature is whether the resulting viscous liquid or gelpossesses characteristics that are required for preventing theabove-noted abuse modalities. For example, in order to prevent drug frombeing released in a dosage form in sufficient quantities to produce thedesired effect of the abuse, a gel must be appropriately viscous anduniform. A gel that is runny or non-uniform (e.g., containing portionsthat are more fluid and portions that are less fluid) will be lesseffective in blocking commonly-attempted forms of abuse and release ofdrug. The present disclosure pertains to dosage forms that produce highquality abuse deterrent features when subjected to attempted abuse. Inbasic terms, the dosage forms that are disclosed herein exhibit animmediate release profile of drug when administered to a human intherapeutic doses, and an extended release profile of drug whenadministered to a human in supratherapeutic doses.

More particularly, it has been discovered that specific ratios ofgelling polymer, particularly carbomer gelling polymer, to pH adjustingcompound within the matrix of the dosage forms can be critical forallowing the dosage form, when administered in supratherapeutic doses,to produce a gel having superior physical characteristics for purposesof thwarting abuse of esketamine from the dosage forms. This finding,among others, is described more fully, infra.

Ideally, the abuse resistant and deterrent features include those thatthwart other commonly used approaches for extracting higher doses ofactive ingredient than would be appropriate pursuant to a therapeuticdosing regimen. One commonly used approach for abusing an activeingredient involves crushing a dosage form and nasally insufflating thecrushed dosage form. As disclosed more fully herein, the presentlydisclosed dosage forms are capable of resisting attempts of this type bylimiting the amount of active ingredient that diffuses across nasalmembranes when the dosage form is crushed and then nasally insufflated.

Another commonly used approach for extracting a higher thantherapeutically appropriate dose of an active ingredient involvesphysically manipulating the dosage form (e.g., crushing it) followed byheating the material that results from the physical manipulation. Theheating step can function to defeat a gelling mechanism that otherwiseprevents the extraction of active ingredient. However, as also describedmore fully herein, the presently disclosed dosage forms preventextraction of active ingredient even when physically manipulated (e.g.,crushed) and subjected to heating.

A further commonly used approach for extracting active ingredientinvolves physically manipulating (e.g., crushing) a dosage form andselectively ingesting particles that have a higher concentration ofactive ingredient and a lower concentration of inactive excipient. Thepresent inventors have discovered that the dosage forms disclosed hereinare able to resist attempts to abuse the dosage form in this additionalmanner, and this feature is described more fully infra.

In the present disclosure, the singular forms “a”, “an”, and “the”include the plural reference, and reference to a particular numericalvalue includes at least that particular value, unless the contextclearly indicates otherwise. Thus, for example, a reference to “afiller” is a reference to one or more of such reagents and equivalentsthereof known to those skilled in the art, and so forth. Furthermore,when indicating that a certain element “may be” X, Y, or Z, it is notintended by such usage to exclude in all instances other choices for theelement.

When values are expressed as approximations, by use of the antecedent“about”, it will be understood that the particular value forms anotherembodiment. As used herein, “about X” (where X is a numerical value)preferably refers to ±10% of the recited value, inclusive. For example,the phrase “about 8” can refer to a value of 7.2 to 8.8, inclusive. Thisvalue may include “exactly 8”. Where present, all ranges are inclusiveand combinable. For example, when a range of “1 to 5” is recited, therecited range should be construed as optionally including ranges “1 to4”, “1 to 3”, “1-2”, “1-2 & 4-5”, “1-3 & 5”, and the like. In addition,when a list of alternatives is positively provided, such a listing canalso include embodiments where any of the alternatives may be excluded.For example, when a range of “1 to 5” is described, such a descriptioncan support situations whereby any of 1, 2, 3, 4, or 5 are excluded;thus, a recitation of “1 to 5” may support “1 and 3-5, but not 2”, orsimply “wherein 2 is not included.”

The entire disclosures of each patent, patent application, andpublication cited or described in this document are hereby incorporatedherein by reference.

Esketamine is the S-enantiomer of the racemic cyclohexanone derivativeketamine, a glutamate N-Methyl-D-aspartate (NMDA) receptor antagonist.It is indicated as an anesthetic, and is approximately twice as potentas an anesthetic as racemic ketamine. The chemical structure ofesketamine is shown below:

Esketamine is a schedule III controlled substance, and can producedissociative and hallucinogenic effects when subjected to misuse orabuse. Thus, there exists a risk of abuse with respect to dosage formscontaining esketamine.

The present disclosure relates, inter alia, to oral dosage formscomprising: (i) a first population of core-shell particles, each of thecore-shell particles of the first population comprising a core thatincludes a gelling polymer and a wax; an active pharmaceutical layersurrounding the core comprising esketamine; and at least one layersurrounding the active pharmaceutical layer, the at least one layercomprising a pH-sensitive film comprising a pH-sensitive polymer that isinsoluble in water at a pH greater than 5; and, (ii) a matrix comprisinga carbomer gelling polymer and sodium bicarbonate, wherein the carbomergelling polymer and sodium bicarbonate are present in said dosage formin a ratio by weight percentage of about 2:2 based on the total weightof the dosage form. The disclosed dosage forms can exhibit an immediaterelease profile of the esketamine when administered to a human intherapeutic doses, and an extended release profile of the esketaminewhen administered to a human in supratherapeutic doses. The term “wt%”as used herein, refers to the weight percentage of a substance, orcombination of substances, based on the total weight of all substancesweighed.

Unless otherwise specified, “esketamine” as used throughout the presentdisclosure can also refer to isotopically-enriched esketamine.“Esketamine” as used herein may also refer to that compound in its freebase form (i.e., base equivalent), or to a salt of the compound, such asesketamine hydrochloride.

As used herein, esketamine that is “isotopically-enriched” refers to acondition in which the abundance of deuterium (²H), ¹³C, or ¹⁵N at anyrelevant site of the compound is substantially more than the abundanceof deuterium, ¹³C, or ¹⁵N naturally occurring at that site in an amountof the compound. A relevant site in a compound as used above is a sitewhich would be designated as “H” or “C” or “N” in a chemical structurerepresentation of the compound when not enriched. The expression,“naturally occurring,” as used above refers to the abundance of theparticular atom which would be present at a relevant site in a compoundif the compound was prepared without any affirmative synthesis step toenrich the abundance of a different isotope. Thus, for example in a“deuterium-enriched” compound, the abundance of deuterium at anyrelevant site in the chemical structure of the esketamine can range froman amount that is substantially more than the natural abundance ofdeuterium (about 0.0115%) all the way up to 100%, for example, fromabout 1% to about 100%, or from about 10% to about 100%, or from about50% to about 100%, or from about 90% to about 100%.

Similarly, for a “¹³C-enriched” compound, the abundance of ¹³C at anyrelevant site in the chemical structure of the API can range from anamount that is substantially more than the natural abundance of ¹³C(about 1.109%) all the way up to 100%, for example, from about 5% toabout 100%, or from about 10% to about 100%, or from about 50% to about100%, or from about 90% to about 100%. Similarly for a “¹⁵N-enriched”compound, the abundance of ¹⁵N at any relevant site in the chemicalstructure of the esketamine can range from an amount that issubstantially more than the natural abundance of ¹⁵N (about 0.364%) allthe way up to 100%, for example, from about 1% to about 100%, or fromabout 10% to about 100%, or from about 50% to about 100%, or from about90% to about 100%.

Isotopically-enriched compounds can generally be prepared byconventional techniques known to those skilled in the art. Suchisotopically-enriched compounds can also be prepared by adaptingconventional processes as described in the scientific literature forsynthesis of esketamine as suitable for formulation according to theinvention, and using an appropriate isotopically-substituted reagent (orreagents) in place of the corresponding non isotopically-substitutedreagent(s) employed in the conventional synthesis of the nonisotopically-enriched compounds. Examples of ways to obtain adeuterium-enriched compound include exchanging hydrogen with deuteriumor synthesizing the compound with deuterium-enriched starting materials.

As used herein, expressions such as “abuse deterrent” and “abuseresistant”, and “preventing”, “deterring”, “resisting”, or “inhibiting”abuse, relate to the ability of features of the claimed formulations toprovide significant physical or chemical impediments to the use of anactive pharmaceutical ingredient for objectives other than its primarytherapeutic indications. The objective in such deterrence includes bothmaking abuse practices significantly more difficult to carry out, andmaking any product resulting from an attempt to carry out such abusepractices on the claimed formulations significantly less desirable, lessprofitable, and less abusable to the potential abuser.

The term “immediate release”, as used herein, refers to a dosage formthat upon oral ingestion by a human releases substantially all of acontained active pharmaceutical ingredient into a gastrointestinal tractfor biological uptake in a short time. In vitro methods of measuring arelease profile of a dosage form, for the purpose of determining whethera dosage form exhibits an immediate release or extended releasedissolution profile, are known in the pharmaceutical arts. By suchmethods, examples of immediate release dosage forms as described hereincan be measured to be capable of releasing substantially all of a totalamount of at least one type of active pharmaceutical ingredient (“API”)(e.g., esketamine), contained in the dosage form (e.g., at least 75, 80,90, 95, 97 or 100 weight percent of the total amount of the API in adosage form) into a solution (e.g., acidic aqueous solution) of asuitable pH within 240 minutes, e.g., in less than 180 minutes, lessthan 90 minutes, or less than 60, 30, 15, or 5 minutes. For example, arelease profile of a dosage form of the present description may bemeasured by a method that exposes the dosage form to a volume of up to900 mL (e.g., 300 mL, 500 mL, or 900 mL, based on various test methods)of hydrochloric acid (from 0.01N to 0.1N), e.g., aqueous hydrochloricacid, at a pH of from 1 to 2, and at a temperature of 37° C. Accordingto some embodiments, the dosage forms described herein release at least90% or at least 95% of API in less than 30 minutes when administered attherapeutic doses (e.g., as one single dosage unit), wherein the releaseprofiles may be evaluated, for example, by dissolution in 500 mL of0.01N HCl media using USP II apparatus at 50 RPM paddle speed and 37° C.In some embodiments, the 0.01N HCl medium is subjected to deaerationbased on the recommendations of USP < 1092>. A release profile of adosage form of the present description may alternatively be measured bya method that exposes the dosage form to a volume of up to 900 mL (e.g.,200 mL, 300 mL, 400 mL, 500 mL, 600 mL, 700 mL, 800 mL, or 900 mL, basedon various test methods) of an aqueous buffer solution (e.g., an acetatebuffer solution) at a pH that is representative of the pH conditions ofa fed stomach, e.g., at a pH of about 4.5, and at a temperature of 37°C., with or without deaeration.

The term “extended release” can be defined as not more than 75% releaseof the API at 30 minutes, wherein the release profiles may be evaluated,for example, by dissolution in 400 mL of 0.1N HCl media using USP IIapparatus at 50 RPM paddle speed and 37° C. In some embodiments, the0.1N HCl medium is subjected to deaeration based on the recommendationsof USP < 1092>.

As used herein, the phrase, “administered in a manner intended to resultin administration of the esketamine in a higher than therapeutic dose”includes administration in a manner that would result in a C_(max) ofesketamine that is higher or significantly higher than a therapeuticC_(max) of esketamine considered to be safe and efficacious for treatinga particular disease or disorder, if the esketamine was administered ina dosage form that did not include the features of a dosage formdescribed herein.

According to some embodiments, the dosage forms described hereindemonstrate (i) not less than 95% of API released in 30 minutes whenadministered at therapeutic doses, wherein the release profile isevaluated by dissolution in 500 mL of deaerated 0.01N HCl media usingUSP II apparatus at 50 RPM paddle speed and 37° C.; and (ii) not morethan 75% release of the API at 30 minutes when administered atsupratherapeutic doses, wherein the release profiles may be evaluated bydissolution in 400 mL of deaerated 0.1N HCl media using USP II apparatusat 50 RPM paddle speed and 37° C. In this context, a “supratherapeuticdose” can be understood to correspond to administration of five or more,six or more, seven or more, eight or more, nine or more, ten or more,eleven or more, or twelve or more individual dose units, e.g., tablets,simultaneously. It will also be understood that administering multipleindividual dose units simultaneously would reasonably includeadministering those multiple doses sequentially over a short timeinterval, e.g., over an interval of less than 60 minutes, less than 30minutes, less than 15 minutes, less than 5 minutes, or less than oneminute.

Dosage forms as described herein can be formulated to provide animmediate release profile of esketamine, while including effective oradvantageous abuse deterrent features that are effective to deter abuseof the API. The combination of immediate release of esketamine withbroad abuse resistance of the same API for multiple abuse modalitiesincluding multi-tablet dosing, as described herein, is not believed tobe previously known. The present dosage forms can also be morespecifically characterized as resistant to certain common methods ofabuse, such as 1) abuse by injection (e.g., by steps that includegrinding a dosage form and dissolving it), 2) abuse by nasalinsufflation (e.g., also by grinding and optionally dissolving thedosage form), and 3) abuse by multi-tablet dosing by oral consumption,meaning simultaneous oral ingestion of multiple, supratherapeuticquantities of orally administered dosage forms such as tablets orcapsules. The third mode of abuse, multi-tablet dosing, is particularlycommon with immediate release dosage forms and is particularly difficultto defend against by design of a dosage form structure or byformulation. Accordingly, the ability of the presently-described dosageforms to prevent or deter abuse (or even accidental overdose) bymulti-tablet dosing represents a particularly noteworthy feature.

In vitro testing as described herein demonstrated that the presentlydisclosed dosage forms provide deterrence against abuse by multi-tabletdosing. More specifically, in vitro testing of exemplary dosage formswas performed by conducting dissolution testing of one or more dosageforms (tablets) in 400 mL of deaerated 0.1N HCL maintained at 37° C.using a 50 RPM paddle speed. See Example 5, infra. As shown in FIG. 4and FIG. 5 , the amount (percentage per tablet) of esketamine releasedin the media is reduced when multiple dosage units are administeredtogether, as opposed to when a single dosage unit is subjected torelease testing. The data also demonstrate that the tested dosage formsare effective to prevent increased levels of esketamine uptake by anindividual who would accidentally ingest multiple tablets, and arethereby effective to prevent or reduce the risk of an unintentionaloverdose of the esketamine.

Accordingly, dosage forms as described herein provide a method ofpreventing or attenuating a short-term concentration spike of esketaminein the bloodstream of a patient who is prescribed the drug, or in thebloodstream of an abuser who consumes the drug for recreationalpurposes, in the event that a patient or the abuser intentionally orunintentionally consumes a supratherapeutic dose of the drug. Thus,dosage forms as described herein can provide a method whereby a drugoverdose may be prevented, reduced, or attenuated when a subjectintentionally or unintentionally consumes a supratherapeutic dose of thedrug. As a result, dosage forms as described herein can provide agreater amount of time for medical intervention in the case ofintentional or accidental overdose by ingestion of a supratherapeuticdose.

A “supratherapeutic dose” refers to a dose that exceeds what wouldnormally be prescribed for therapy with respect to a particular diseaseor disorder, e.g., a dose that results in a C_(max) that exceeds whatwould normally be needed for effective therapy of the particular diseaseor disorder. For example, a supratherapeutic dose may represent four,five, six, seven, eight, nine, ten, eleven, twelve, or more than twelveindividual dosage units (e.g., tablets, capsules, and the like).

Dosage forms as described herein can include one or more gellingpolymers. A gelling polymer can act as an abuse deterrent feature bycompromising abuse practices involving dissolution of the activepharmaceutical ingredient of the dosage in a small volume of solvent inan attempt to render the API more accessible or easily isolatable. Agelling polymer can deter or prevent abuse of the esketamine byincreasing the viscosity of a combination of the ground dosage form withsolvent to an extent that is sufficient to prevent the combination orthe esketamine from being taken up by and injected using a syringe. Whenexposed to a volume of solvent such as a C₁₋₄ alcohol (e.g., ethanol) orwater, a gelling polymer from a ground (e.g., crushed) dosage form canform a non-injectable mass that ranges in type from an insoluble mass,to a gel, to a viscous slurry, that exhibits a viscosity thatsubstantially prevents uptake by or injection from a needle of ahypodermic syringe.

Suitable gelling polymers include one or a combination of polymers that,as part of a dosage form, upon contact of the dosage form with a volumeof solvent, absorb the solvent and swells to form a viscous orsemi-viscous substance that significantly reduces or minimizes theamount of free solvent that can contain an amount of a solubilizedesketamine and that can be drawn into a syringe. The gelled polymer canalso or alternatively function to reduce the overall amount of drug thatis extractable with the solvent by entrapping the drug in a gel matrix.

At the same time, the gelling polymers used herein do not interfere withdesired dissolution of the dosage forms, the desired release (immediaterelease) of esketamine from the dosage forms, or the uptake of theesketamine by a patient ingesting the intact immediate release dosageform for an intended therapeutic purpose. The gelling polymer may bepresent in the dosage forms within a core-shell particle that includesactive pharmaceutical ingredient, such as in a core or in a layer(“shell”) surrounding the core, wherein an amount of activepharmaceutical ingredient is contained within the core, in a layer thatis coated core, or both. Another exemplary location is within a matrix.Gelling polymer may also or alternatively be present in a core-shellparticle that does not include esketamine, such as in the core, or in alayer surrounding the core.

The gelling polymer can be present in a dosage form at any desiredamount and within any portion of the present dosage forms. The amount ofgelling polymer can be any useful amount, meaning an amount that canproduce an abuse-deterrent viscous mixture or gel if the dosage form iscrushed, ground, powdered, or otherwise similarly manipulated, and mixedwith solvent. A useful amount of total gelling polymer in a dosage formmay be in a range from 0.5 to 90 weight percent gelling polymer based ona total weight of the dosage form, e.g., from 0.7 to 20, 1 to 20, 2 to15, 2 to 10, or 3 to 7 weight percent gelling polymer based on totalweight of the dosage form.

The presently disclosed dosage forms include core-shell particles, andthe cores of such particles preferably contain a gelling polymer. A core(uncoated) of a core-shell particle can contain any useful amount ofgelling polymer, up to and including 100 percent gelling polymer in acore of a core-shell particle, e.g., from 10 to 95 weight percentgelling polymer based on the total weight of the core, such as 20 to 90,25 to 85, 30 to 85, 40 to 85, 40 to 80, 45 to 75, 50 to 75, 55 to 70, 55to 65, or 57 to 62 weight percent gelling polymer based on the totalweight of the core.

Described in terms of total weight of a dosage form, an amount ofgelling polymer present in a core of a core shell polymer may be, e.g.,in a range from 0.5 to 15 weight percent gelling polymer (present in thecore) per total weight of the dosage form, such as from 1 to 10 weightpercent gelling polymer (present in the core) per total weight dosageform.

In certain embodiments, gelling polymer may also or alternatively beprovided in the matrix portion of the present dosage forms. The types ofgelling polymers in the respective portions of the present dosage formsmay be the same or different. For example, when present, the gellingpolymer in the core of the core-shell particles may be the same or adifferent type as a gelling polymer in the matrix of the dosage form.

A gelling polymer for use in the present dosage forms can be anypolymeric material that exhibits the ability to retain a significantfraction of adsorbed solvent in its molecular structure, e.g., thesolvent being a solvent otherwise useful by an abuser to extract APIfrom a dosage form or a crushed or powdered dosage form, the solvent forexample being water or a C₁ to C₄ alcohol such as ethanol or methanol.Exemplary gelling polymers include materials that can swell or expand toa very high degree when placed in contact with such a solvent. Theswelling or expansion may cause the gelling polymer to experience from atwo- to one-thousand-fold volume increase relative to the dry state.More specific examples of gelling polymers include swellable polymerssometimes referred to as osmopolymers or hydrogels. The gelling polymermay be non-cross-linked, lightly crosslinked, or highly crosslinked. Thecrosslinking may involve covalent or ionic bonds with the polymerpossessing the ability to swell in the presence of a solvent, and whencross-linked will not dissolve in the solvent.

A gelling polymer, upon dissolution or dispersion in an aqueous solutionor dispersion (e.g., water) at a concentration of 2% w/w (based on thedry material), preferably creates a solution/dispersion with a viscosityof from about 100 to about 200,000 mPa·s (e.g., 4,000 to 175,000 mPa·s,and 4,000 to 50,000 mPa·s) as measured at 20° C. (+/-0.2 degree Celsius)using the analysis method described in the USP 33 monograph forHypromellose, incorporated herein by reference.

Generally suitable gelling polymers include pharmaceutically acceptablepolymers that undergo an increase in viscosity upon contact with asolvent, as described. Various examples of polymers are known to beuseful in this manner, generally including natural and syntheticstarches (i.e., modified or pregelatinized modified starch), natural andsynthetic celluloses, acrylates, and polyalkylene oxides. Examples ofnatural starches include natural starches include corn starch, potatostarch, rice starch, tapioca starch and wheat starch, hydroxypropylstarch such as hydroxypropyl corn starch, hydroxypropyl pea starch andhydropropyl potato starch (derivative of natural starch). Examples ofsynthetic starches, i.e., modified or pregelatinized modified starch,include acetylated distarch adipate, waxy maize basis, acid-treatedmaize starch, acid-treated waxy maize starch, distarch phosphate, waxymaize basis, oxidized waxy maize starch, and sodium octenyl succinatestarch. Examples of celluloses include carboxymethyl cellulose calcium,carboxymethylcellulose sodium, ethycellulose, methylcellulose, celluloseethers such as hydroxypropyl cellulose, hydroxyethylcellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose,carboxymethylcellulose sodium, and low substituted hydroxypropylcellulose. Examples of acrylates include Eudragit RS, RL, NE, NM.Examples of polyalkylene oxides include polyethylene oxide such asPOLYOX N10, N80, N60K, WSR-1105 LEO, or WSR-301 LEO, or WSR-303 LEO.

Accordingly, examples of suitable gelling polymers for use in anycomponent of the present dosage forms include, among others,polyethylene oxide, polyvinyl alcohol, hydroxypropyl methyl cellulose,hydroxypropyl cellulose, methyl cellulose, hydroxyethyl methylcellulose, sodium carboxymethylcellulose, hydroxyethyl cellulose, andpolyacrylic acid, and other high molecular weight polymers capable ofattaining a viscosity level effective to prevent uptake in a syringe, ifcombined with a small volume of solvent as described.

Other examples of suitable gelling polymers can include, if ofsufficiently high molecular weight: ethylcellulose, cellulose acetate,cellulose acetate propionate, cellulose acetate butyrate, celluloseacetate phthalate and cellulose triacetate, cellulose ether, celluloseester, cellulose ester ether, cellulose; acrylic resins comprisingcopolymers synthesized from acrylic and methacrylic acid esters, forexample acrylic acid and methacrylic acid copolymers, methylmethacrylate copolymers, ethoxyethyl methacrylates, cyanoethylmethacrylate, poly(acrylic acid), poly(methacrylic acid), methacrylicacid alkylamide copolymer, poly(methyl methacrylate), polymethacrylate,poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkylmethacrylate copolymer, poly(methacrylic acid anhydride), and glycidylmethacrylate copolymers.

Exemplary gelling polymers also include natural polymers such as thosederived from a plant or animal, as well as polymers preparedsynthetically. Examples include polyhydroalkylcellulose having amolecular weight greater than 50,000; poly(hydroxy-alkylmethacrylate)having a molecular weight of from 5,000 to 5,000,000;poly(vinylpyrrolidone) having a molecular weight of from 100,000 to3,000,000; anionic and cationic hydrogels; poly(electrolyte) complexes;poly(vinyl alcohol) having a low acetate residual; a swellable mixtureof agar and carboxymethyl cellulose; a swellable composition comprisingmethyl cellulose mixed with a sparingly cross-linked agar; a polyetherhaving a molecular weight of from 10,000 to 6,000,000; water-swellablecopolymer produced by a dispersion of finely divided copolymer of maleicanhydride with styrene, ethylene, propylene, or isobutylene; waterswellable polymer of N-vinyl lactams; and the like.

Other polymers useful as gelling polymers include pectin having amolecular weight ranging from 30,000 to 300,000; polysaccharides such asagar, acacia, karaya, tragacanth, algins and guar; polyacrylamides;water-swellable indene maleic anhydride polymers; Good-rite® polyacrylicacid having a molecular weight of 80,000 to 200,000; Polyox®polyethylene oxide polymers having a molecular weight of 100,000 to7,000,000; starch graft copolymers; Aqua-Keep® acrylate polymers withwater absorbability of 400 times its original weight; diesters ofpolyglucan; a mixture of cross-linked polyvinyl alcohol andpoly(-vinyl-2-pyrrolidone); poly(ethylene glycol) having a molecularweight of 4,000 to 100,000.

In certain embodiments, a gelling polymer may include hydroxypropylmethyl cellulose (e.g., Hypromellose or HPMC), and hydroxy methylcellulose, methyl cellulose, hydroxyethylmethyl cellulose, or sodiumcarboxymethyl cellulose. When present, a hydroxypropyl methyl cellulosecan have a molecular weight ranging from 10,000 to 1,500,000. Examplesof suitable, commercially available hydroxypropyl methylcellulosepolymers include HPMC K100M, Methocel K100LV and Methocel K4M.

A specific class of gelling polymer of which one or more members may beused in the present dosage forms is carbomer polymers, which arepolymers derived from acrylic acid (e.g., acrylic acid homopolymers) andcrosslinked with polyalcohol allyl ethers, e.g., crosslinked withpolyalkenyl ethers of pentaerythritol or sucrose. Carbomer polymers arehydrophilic and are not substantially soluble in water. Rather, thesepolymers swell when dispersed in water forming a colloidal,mucilage-like dispersion. Carboxyl groups provided by acrylic acidresidues of the polymer backbone are responsible for certain behavior ofthe polymers. Particles of this polymer can be viewed as a networkstructure of polymer chains interconnected by crosslinks. The structurecan swell in water by up to one thousand times of an original (dry)volume (and ten times an original diameter of polymer particles) to forma gel when exposed to a pH environment above 4-6. The pKa of thesepolymers can be 6 ± 0.5. Accordingly, carboxylate groups pendant fromthe polymer backbone can ionize at a pH above 6, producing a repulsionbetween the negatively-charged particles, which adds to the swelling ofthe polymer if exposed to solvent at this pH range.

For this reason, the presently disclosed dosage forms can include a pHadjuster in an amount and location within the dosage form to raise thepH of a carbomer polymer to at least 6, to substantially neutralize thecarboxylate groups. Exemplary types and amounts of pH adjusters arediscussed more fully, infra.

Carbomer polymers are often referred to in the art using alternativeTerminology such as, for example, carbomer homopolymer, acrylic acidpolymers, carbomer, Carboxy polymethylene, carboxyvinyl polymer,polyacrylic acid, and poly(acrylic acid), The USP-Nf lists threeumbrella monographs i.e. For “carbomer copolymer,” for “carbomerhomopolymer,” and for “carbomer interpolymer.”

Certain carbomer polymers that may be useful as a gelling polymer canhave an average equivalent weight of 76 per carboxyl group. Examples ofsuitable commercially available carbomers include Carbopol® 934, 934PNF, Carbopol® 974P NF and Carbopol® 971P NF, Carbopol® 940, andCarbopol® 941, Carbopol® 71G, commercially available from Lubrizol.Examples of such polymers are described in U.S. Pat. Nos. 2,798,053 and2,909,462, the entireties of which are incorporated herein by reference.Theoretical molecular weight ranges of Carbopol® products are in a rangefrom 700,000 to 3 billion, theoretical estimation. For dosage forms asdescribed herein, a gelling polymer (e.g., Carbopol®) can have amolecular weight and viscosity-increasing performance that will reduceor substantially inhibit an ability of an abuser to extract API from acombination of dosage form and a small volume of solvent, as described,while also being capable of being processed into a compressed dosageform.

A gelling polymer can also be characterized by viscosity of a solutionprepared from the gelling polymer. Product information for commerciallyavailable Carbopol® polymers reports that viscosities of differentCarbopol® polymers are as follows:

Type of Carbomer Viscosity specified (cP) Carbomer Homopolymer Type A(compendial name for Carbopol® 71G, Carbopol® 971P and Carbopol® 981)4,000 - 11,000 Carbomer Homopolymer Type B (compendial name forCarbopol® 934P, and Carbopol® 934) 25,000 - 45,000 Carbomer HomopolymerType C (compendial name for Carbopol® 980) 40,000 - 60,000

(Type A and Type B viscosities measured using a Brookfield RVT, 20 rpm,neutralized to pH 7.3-7.8, 0.5 weight percent mucilage, spindle #5.)

A further exemplary gelling polymer is the class of xanthan gumpolymers, which includes natural polymers useful as hydrocolloids, andderived from fermentation of a carbohydrate. A molecular weight of aXanthan gum may be approximately 1,000,000. Xanthan gum has been shownto provide particularly useful extraction resistance in a dosage form asdescribed, and therefore may be preferred in dosage forms as described,especially if present in an amount of at least 2 or 3 weight percentbased on a total weight of a dosage form.

Without limiting the scope of useful gelling polymers to any specifictype or molecular weight, examples of useful gelling polymers, anduseful respective molecular weights, are shown below.

Gelling Polymer Weight Average Molecular Weight Carbomer 700,000 to 3billion (estimated) HPMC 2910 K types 164,000 - 1,200,000 HPMC 2910 Etypes 20,000 - 746,000 hydroxyethylcellulose 90,000 - 1,300,000ethylcellulose 75,000 - 215,000 carboxymethylcellulose 49,000 - 725,000sodium carboxymethylcellulose 49,000 - 725,000 povidone 4,000 -1,300,000 copovidone 47,000 hydroxypropyl cellulose 40,000 - 1,150,000xanthan gum 1,000,000 polyethylene oxide Average molecular wt: 100,000 -7,000,000

The present dosage forms may optionally include another abuse deterrentfeature in the form of a wax, such as a wax/fat material, e.g., asdescribed in U.S. Pat. No. 8,445,018, the entirety of which isincorporated herein by reference. The wax can be a solid wax materialthat is present in the dosage form at a location that inhibits an abuserfrom crushing, grinding, or otherwise forming the dosage form into aground powder that might be abused by a nasal insufflation mode, or fromwhich active pharmaceutical agent can be easily accessed and removedsuch as by dissolution or extraction using a solvent.

A wax may be present in the dosage form at a location and in an amountto also not interfere with desired uptake of the active pharmaceuticalingredient by a patient upon oral ingestion, in an immediate releasedosage form. An exemplary location is at a core of a core-shellparticle, especially a core that also contains gelling polymer and thateither may or may not contain active pharmaceutical ingredient. In oneembodiment, a wax is provided in the core of core-shell particles in thepresent dosage forms, along with a gelling polymer, in the absence ofesketamine in the core. Wax located at a core of a particle (e.g., acore-shell particle) that also includes active pharmaceutical ingredient(e.g., at a layer covering the core, or within the core) will becomemixed with the active pharmaceutical ingredient upon crushing orgrinding, etc., of the particle. In one embodiment, a wax is provided inthe core of core-shell particles in the present dosage forms, along witha gelling polymer, in the absence of esketamine in the core. Wax that islocated at a core of such a particle (e.g., a core-shell particle)wherein the core does not contain API will also become mixed with theAPI (e.g., API present in API-containing core-shell particles that arealso present in the dosage form) upon destructive manipulation (e.g.,crushing or grinding) of the dosage form. When the wax is mixed with theactive pharmaceutical ingredient, the active ingredient is inhibited orprevented from becoming thereafter dissolved in a solvent such as water,or otherwise efficiently accessed by an abuser.

A core (uncoated) of a core-shell particle can contain any useful amountof wax, up to and including 100 percent wax, e.g., from 0.1 to 85 weightpercent wax based on the total weight of the core, such as 5 to 80, 10to 70, 15 to 60, 20 to 50, 20-40, or 20-30, or in an amount of about 5,10, 15, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,36, 37, 38, 39, 40, 45, 50, 55, 60, 65, 70, 75, or 80 weight percentwax, based on the total weight of the core.

The wax may be a wax (e.g., fat) material that is generally hydrophobicand that may be either solid or liquid at room temperature, preferablysolid at room temperature (25° C.). Generally useful fats include thosehydrophobic materials that are fatty acid-based compounds generallyhaving a hydrophilic/lipophilic balance (HLB) of 6 or less, morepreferably 4 or less, and most preferably 2 or less. A fat can have anymelting temperature, with preferred fats being solid at room temperatureand having a melting point that is at least 30° C., e.g., at least 40°C., e.g., at least 50° C. Useful fats include fatty acids and fattyesters that may be substituted or unsubstituted, saturated orunsaturated, and that have a chain length of at least 10, 12, or 14carbons. The esters may include a fatty acid group bound to any of analcohol, glycol, or glycerol. With regard to glycercols, for example,mono-, di-, and tri-fatty substituted glycerols can be useful as well asmixtures thereof.

Suitable wax ingredients include fatty acid esters, glycerol fatty acidesters, fatty glyceride derivatives, waxes, and fatty alcohols such as,for example, glycerol behenate (also referred to as glyceryl behenate,glycerin behenate, or glycerol docosanoate) (available commercially asCOMPRITOL®), glycerol palmitostearate (PRECIROL®), glycerolmonostearate, stearoyl macroglycerides (GELUCIRE® 50/13). Other waxesmore generally include insect and animal waxes, vegetable waxes, mineralwaxes, petroleum waxes, and synthetic waxes; particularly examplesinclude beeswax, carnauba wax, candelilla wax, montan wax, ouricury wax,rice-bran wax, jojoba wax, microcrystalline wax, cetyl ester wax, cetylalcohol, anionic emulsifying wax, nonionic emulsifying wax and paraffinwax.

The dosage form may optionally include another component contributing toabuse deterrence in the form of a filler or binder material provided ina manner to compromise abuse practices wherein an abuser crushes,grinds, or otherwise forms the dosage form into a ground powder thatmight be abused by nasal insufflation, or from which activepharmaceutical agent can be easily accessed and removed such as bydissolution or extraction using a solvent.

The binder or filler may be present in the dosage form at a location andin an amount to not interfere with desired uptake of the activepharmaceutical ingredient by a patient upon oral ingestion, in animmediate release dosage form. An exemplary location is at a core of acore-shell particle. Suitable filler or binder located at a core of acore-shell particle that also includes active pharmaceutical ingredient(such as in a layer covering the core, or within the core) will becomemixed with the active pharmaceutical ingredient upon destructivemanipulation (e.g., crushing or grinding) of the particle. As discussedpreviously, the dosage form may also include core shell particles thatdo not contain esketamine. A filler or binder that is located at a coreof such a particle that does not contain API will also become mixed withthe API (e.g., API present in API-containing core shell particles thatare also present in the dosage form) upon manipulation (e.g., crushingor grinding) of the dosage form. When a filler or binder is mixed withthe active pharmaceutical ingredient, the active pharmaceuticalingredient is inhibited or prevented from becoming thereafter dissolvedin a solvent such as water or otherwise efficiently accessed by anabuser.

When present within the core of a core-shell particle of the presentdosage forms, filler or binder may be present in any useful amount, upto and including 100 percent filler or binder (singly or in combination)in a core of a core-shell particle. For example, filler or binder may bepresent in the core of a core-shell particle in an amount of from 5 to95 weight percent filler or binder based on total weight of the core,such as from 5 to 70, 5 to 50, 7 to 40, 10 to 30, 10 to 20, 10 to 17, 12to 17, or 13 to 16 weight percent, or in an amount of about 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, or 80 percent by weightbased on the total weight of the core. Examples of cores that containhigh levels of filler include spherical particles that contain 100percent sugar, and spherical particles that contain 100 percentmicrocrystalline cellulose. Inert spherical filler products such asthese, having useful particle sizes, are commercially available underthe trade name Celphere®, and under the trade name Suglets® (sugarspheres, also containing starch), including as follows: CELPHERE SCP-100(Particle size (µm) 75-212); CELPHERE SCP-102 (Particle size (µm)106-212); CELPHERE SCP-203 (Particle size (µm) 150-300); CELPHERESCP-305 (Particle size (µm) 300-500); CELPHERE SCP-507 (Particle size(µm) 500-710); CELPHERE SCP-708 (Particle size (µm) 710-850). Theparticle sizes of these can be considered to be useful for any core asdescribed herein, prepared of any single filler, gelling polymer,binder, any combination thereof, or any single or combination ofmaterials combined with API.

Another abuse deterrent feature that can be included in a dosage form asprovided herein is a film layer or coating as part of the core-shellparticles that is located over and surrounds the portion of theparticles that contains the active pharmaceutical ingredient. When thedosage forms contain core-shell particles that do not contain an API,the film layer may be present as a layer or coating on such core-shellparticles, as well. The film layer can be any film layer capable ofbeing applied as a partial or complete film layer to core-shellparticles, and to surround API (where present).

The film layer may be prepared from, and will include anypharmaceutically acceptable film forming polymer material, such as oneor more of a binder (e.g. as described herein, such as hydroxypropylcellulose, poly(methyl methacrylates), ethyl cellulose, hydroxypropylmethyl cellulose, hydroxyl methyl cellulose, polyvinyl alcohol, and thelike), a solvent-resistant layer, and a pH-sensitive layer (alsosometimes referred to as a reverse enteric material or layer), e.g.,Eudragit® E 100. The film layer may include any one of these materialsalone (e.g., a film layer may include 100 percent of a single one ofthese types of materials), or a film layer may include a combination oftwo or more of these types of materials.

A solvent-resistant layer is a film layer that retards or preventsrelease of a drug in a solvent (e.g., one or more of water, ethanol, andmethanol) while still allowing the drug to release normally in agastrointestinal tract when ingested as an immediate release oral dosageform. This type of abuse deterrent feature, e.g., solvent-resistantfilm, can inhibit access to an API of a dosage form by preventing orimpeding an abuser from dissolving an intact or powdered dosage form ina solvent type that is often used by an abuser (e.g., water, ethanol,methanol). At the same time, the solvent-resistant film can dissolve ina human gastrointestinal tract with sufficient rapidity to allow for animmediate release profile. As an abuse deterrent feature this type ofsolvent-resistant film covers and encloses API of a core-shell particleand acts as a film barrier or retardant to prevent or retard access tothe API by use of solvent.

A solvent-resistant film is one that does not readily or immediatelydissolve in a small volume of a solvent of the type often used by anabuser to dissolve an API, such as any one of water or a C₁-C₄ alcoholsuch as ethanol or methanol. A “small volume” refers to an amount ofsuch a solvent that can contain an amount of dissolved API that issufficiently concentrated to be useful to an abuser to realize theintended biological effect of the drug abuse, and that is also capableof being administered for abuse of the API, e.g., a volume that cancontain an amount (concentration) of API that is effective to achieve adesired “high” if administered by injection or nasal insufflation, thevolume also being sufficiently small to allow the volume to beadministered by injection or nasal insufflation. For a dosage form to beuseful for abuse as such, an API in the dosage form must be capable ofbeing accessed and dissolved at sufficient concentration by an abuserwithout undue complication, into a “small volume” of solvent, which is avolume that can be administered by injection or by nasal insufflation.Generally, a “small volume” of solvent means 50 milliliters or less, or20 milliliters or less, or 10 milliliters or less, or 5 milliliters orless (volumes which could be injected or used for nasal insufflation).

A solvent-resistant film layer can be a film placed on a core-shellparticle that is difficult to dissolve in a “small volume” of water or aC₁-C₄ alcohol such as ethanol or methanol, e.g., that does notimmediately dissolve in one or more of water or any one of a C₁-C₄alcohol, such as methanol or ethanol. The solvent-resistant film therebyretards or prevents an abuser from accessing an API portion of acore-shell particle if the core-shell particle is placed in one of thesesolvents. The solvent-resistant film need not be completely orsubstantially insoluble in any one of these solvents, or in all of thesolvents, and it must be capable of allowing the API to be accessed withsufficient rapidity, in a gastrointestinal tract, for the dosage form tobe useful as an immediate release dosage form.

A particular example of a solvent-resistant film is a film that exhibitssolubility properties that depend on the pH of a solvent. An example ofa solvent-resistant film may be a film that is substantially orcompletely insoluble at a pH that is greater than a pH condition of ahuman stomach, and that is sufficiently soluble at a pH condition of astomach (and gastrointestinal tract) to allow the film to dissolve andrelease API with sufficient rapidity that the dosage form can be usefulas an immediate release oral dosage form. A pH-sensitive layer is a typeof solvent-resistant film, and can be disposed in a dosage form tosurround an active pharmaceutical ingredient and inhibit or preventaccess to and dissolution of the active pharmaceutical ingredient in asolvent outside of a stomach (e.g., at a neutral pH environment), whilestill allowing the active pharmaceutical ingredient to be efficientlyreleased from an immediate release dosage form at a lower pH environmentof a user’s stomach. This type of abuse deterrent feature can prevent orsignificantly impede an abuser’s access to an active pharmaceuticalagent of a dosage form (e.g., at the core of a core-shell particle or ina layer disposed on the core, or in both the core and the layer disposedon the core) by use of a solvent that is outside of a stomach and thatdoes not have a relatively acidic pH, such as water or a C₁-C₄ alcoholsuch as ethanol or methanol, or a mixture thereof, having a pH that ishigher than a pH found in a human stomach, for example a pH greater than4, greater than 5, or greater than 5.5, or greater than 6.

A pH-sensitive layer may be useful as a solvent-resistant film, placedin a dosage form as a layer of a core-shell particle to surround, cover,or enclose a portion of the core-shell particle that contains activepharmaceutical ingredient. For example, in a core-shell particle, anactive pharmaceutical ingredient may be located at a core or in a layeroutside of an uncoated or coated core, and a solvent-resistant film inthe form of a pH-sensitive layer may be disposed as a separate layersurrounding or covering the portion of the core-shell particle thatcontains the active pharmaceutical ingredient. The pH-sensitive layermay be in direct contact with (adjacent to) a core or a layer thatincludes active pharmaceutical ingredient. Alternatively, a core-shellparticle may include one or more intermediate layers between apH-sensitive layer and a core or layer that includes activepharmaceutical ingredient. In addition, a pH-sensitive layer may beincluded in the dosage form as a layer of a core-shell particle thatdoes not contain either an API layer or any API.

A useful pH-sensitive layer may include a polymer or other material thatcan be placed as a layer of a particle as described herein, such as tocover a more inner layer or core that contains active pharmaceuticalingredient, to form a pH-sensitive film surrounding or covering activepharmaceutical ingredient. The pH-sensitive film can be solubilized byexposure to a liquid that exhibits a pH that may be present in a stomachof a user of the dosage form, such as a pH below 6 or below 5.5. Tofunction as an abuse-deterrent feature, i.e., to inhibit or preventefficient access to the active pharmaceutical ingredient by exposing thedosage form (optionally ground or powdered) to an easily-availablesolvent, the pH-sensitive layer can contain polymer that is not easilyor substantially soluble at a pH that is higher than a pH found in ahuman stomach, e.g., a pH greater than 6. By being insoluble at a pHgreater than 6, the pH-sensitive polymer will not dissolve in manysolvents that are readily available and commonly used by attemptedabusers to extract a water-soluble drug from a dosage form. Examples ofsuch solvents include water, ethanol, and methanol.

Examples of pH-sensitive polymers that may be used in a pH-sensitivelayer in the present dosage forms include the class of reverse entericpolymers that contain cationic-functional groups and that exhibitpH-dependent solubility as described herein. Examples include polymersthat contain basic functional groups, such as amino groups, and thatexhibit solubility at pH conditions found in a (human) stomach but notat relatively higher pH conditions, e.g., not above a pH of 4, 5, or5.5, or not above a pH of 6. More specific examples of such pH-sensitivepolymers include copolymers of dimethyl aminoethyl methacrylates, andneutral methacrylic acid esters; e.g., dimethyl aminoethyl methacrylate,butyl methacrylates, and methyl methacrylates, such as at a ratio of2:1:1. Examples of such polymers are commercially available under thetrade name Eudragit® E 100, Eudragit® E PO, Eudragit® E 12.5, andsimilar amino-functional pH-sensitive polymers. A preferred pH-sensitivepolymer is the polymer Eudragit E 100, but any polymer that issufficiently hydrophilic at a low pH and hydrophobic at a higher pH toexhibit pH-dependent solubility, may also be effective if otherwiseacceptable for use in a pharmaceutical dosage form, for example, as anon-toxic ingredient of an oral dosage form. Reverse entericcompositions are also described in EP 1694724 B1, titled “pH SensitivePolymer and Process for Preparation Thereof”, incorporated herein byreference.

When present in a coating layer of a core-shell particle, whether thatparticle contains active pharmaceutical ingredient or not, asolvent-resistant film layer may be present at any amount useful as anabuse deterrent feature, such as in a range from 0.1 to 90 weightpercent of a total weight of a core-shell particle, e.g., from 3 to 50,10 to 50, 20 to 50, 25 to 45, 25 to 40, 30 to 40, or 30 to 35 weightpercent, or in an amount of about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49,50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 weight percent, relativeto the total weight of the core-shell particle. More generally, a usefulamount solvent-resistant film layer or polymer in a dosage form may bein a range from 1 to 50 weight percent solvent-resistant film layer orpolymer based on a total weight of a dosage form, e.g., from 2 to 30 orfrom 3 to 15 weight percent solvent-resistant polymer based on totalweight dosage form.

A dosage form as presently described further includes a disintegrant,which functions to cause the dosage form to expand and break up duringuse, e.g., under the conditions within a human stomach, to allow theactive pharmaceutical ingredient of the dosage form to be released in amanner to achieve an immediate release profile. Disintegrants are knowningredients of pharmaceutical dosage forms, with various examples beingknown and commercially available. Examples of disintegrants includecompositions of or containing sodium starch glycolate, starch (e.g.,maize starch, potato starch, rice starch, tapioca starch, wheat starch,corn starch and pregelatinized starch), croscarmellose sodium,crospovidone (crosslinked polyvinyl N-pyrrolidone or PVP) (polyplasdoneXL-10), sodium starch glycolate (EXPLOTAB® or PRIMOJEL®), anycombination of the foregoing, and other pharmaceutically acceptablematerials formed into particles having a particle size, density, andother characteristics that are suitable to allow processing of thedisintegrant into a useful immediate release dosage form.

The disintegrant can be present in an immediate release dosage form atany location that allows the disintegrant to function as desired, toexpand within the intact dosage form, upon ingestion, to cause theingested dosage form to break apart and allow for desired immediaterelease of active pharmaceutical ingredient from the dosage form, in astomach. An exemplary location for the disintegrant can be within thematrix, where it can function as an excipient used to contain thecore-shell particles in a dosage form such as a compressed tablet orcapsule.

When included as an excipient of a dosage form, a disintegrant may bepresent in an amount useful to achieve immediate release of an API of adosage form. For example, the disintegrant may be present in an amountof 0.5 to 50, 5 to 40, 10 to 35, 15 to 30, 15 to 25, 17 to 22, or 19 to21 weight percent, or in an amount of about 5, 10, 12, 14, 16, 18, 19,20, 21, 22, 24, 26, 28, 30, 35, 40, 45, or 50 weight percent, based on atotal weight of the dosage form. The amount of disintegrant in thematrix of a dosage form can be consistent with these amounts. Forexample, disintegrant can be included in a matrix (e.g., total of adosage form that is other than the core-shell particles) of a dosageform in an amount in a range from 0.5 to 50 weight percent disintegrantbased on a total weight of the matrix, for example, 1 to 30 weightpercent disintegrant based on total weight matrix.

The presently disclosed dosage forms can also include a pH adjuster. ApH adjuster can be included at a location of the dosage form to affectpH at a specific location of the dosage form that is only a portion of atotal dosage form. As an example, a pH adjuster in the form of a basemay be included at a location of a gelling polymer that contains acidfunctionalities, to neutralize the acid functionalities. Suitable agentsthat can act as a pH adjuster include, for example, phosphate bufferingagents such as, disodium hydrogen phosphate, sodium dihydrogen phosphateand the equivalent potassium salts; carbonate or bicarbonate salts, suchas sodium bicarbonate, sodium carbonate, potassium bicarbonate,potassium carbonate, magnesium carbonate and calcium carbonate;hydroxide bases such as, sodium hydroxide, potassium hydroxide, ammoniumhydroxide; and amine bases such as, triethanolamine, tromethamine,aminomethyl propanol, and tetrahydroxypropyl ethylenediamine.

The amount of pH-adjuster included at the location of the gellingpolymer can be an amount effective to neutralize the acidfunctionalities of the gelling polymer at that location. Morespecifically, a component of a dosage form as described that includes anacid-functional gelling polymer such as a carbomer may include a base inan amount and location to neutralize the acid functionalities of thatpolymer. The pH-adjuster can be located at a location effective to causesuch neutralization, e.g., at the location of the dosage form thatcontains the acid-functional gelling polymer, for example at a core of acore-shell particle or as part of a matrix.

According to some embodiments, the pH adjuster is in the present dosageforms in an amount that is from about 0.5 to about 5 percent by weight,from about 1 to about 4 percent by weight, from about 1.5 to about 4percent by weight, from about 2 to about 3 percent by weight, or in anamount of about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5 percent byweight, based on the total weight of the dosage form.

According to some embodiments, the pH adjuster is in the present dosageforms in an amount that is from about 0.5 to about 2 percent by weight,from about 1 to about 2 percent by weight, from about 1.5 to about 2percent by weight, or in an amount of about 0.5, 1, 1.5, or 2 percent byweight, based on the total weight of the dosage form.

In one embodiment, the pH adjuster is in the dosage form in an amount ofno more than 2 percent by weight. As used throughout the presentdisclosure, “the pH adjuster is in the dosage form in an amount of nomore than 2 percent by weight” includes those embodiments that do notinclude a pH adjuster, i.e., wherein the pH adjuster is 0 percent byweight. In one embodiment, the pH adjuster is in the dosage form in anamount of no more than 2 percent, no more than 1.9 percent, no more than1.8 percent, no more than 1.7 percent, no more than 1.6 percent, no morethan 1.5 percent, no more than 1.4 percent, no more than 1.3 percent, nomore than 1.2 percent, no more than 1.1 percent, no more than 1 percent,no more than 0.9 percent, no more than 0.8 percent, no more than 0.7percent, no more than 0.6 percent, no more than 0.6 percent, no morethan 0.5 percent, no more than 0.4 percent, no more than 0.3 percent, nomore than 0.2 percent, or no more than 0.1 percent by weight.

In one embodiment, the present dosage form comprises a pH adjuster in anamount that is less than 0.1 percent by weight.

In one embodiment, the present dosage form does not comprise a pHadjuster.

As noted above, it has presently been discovered that specific ratios ofgelling polymer, particularly carbomer gelling polymer, to pH adjustingcompound, within the matrix of the present dosage forms can be criticalfor allowing the dosage form, when administered in supratherapeuticdoses, to produce a gel having superior physical characteristics forpurposes of thwarting abuse of esketamine from the dosage forms. In oneembodiment, the dosage form includes a matrix that includes a carbomergelling polymer and a pH adjuster that are present in a ratio of 2:2weight percent, based on the total weight of the dosage form. Forexample, the dosage form can include a matrix that includes a carbomergelling polymer and sodium bicarbonate pH adjuster that are present in aratio of 2:2 weight percent, based on the total weight of the dosageform. As described more fully in the Examples that follow, the gels thatresult from such dosage forms when administered in supratherapeuticdoses possess traits that are optimal for functioning as an abusedeterrent feature, as compared with gels that are formed followingadministration of previous dosage forms in supratherapeutic doses.

For example, with respect to the dosage forms that contain a carbomergelling polymer and sodium bicarbonate pH adjuster that are present in aratio of 2:2 weight percent, based on the total weight of the dosageform, supratherapeutic doses of such dosage forms can produce a gel in15 minutes or less, such as in 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4,3, 2, or 1 minute following exposure to an aqueous medium comprising0.025 N HCl and 70 mM NaCl at 37° C. The supratherapeutic dose may be,for example, 15, 14, 13, 12, 11, 10, 9, or 8 individual dosage units.

In certain embodiments, the dosage forms are such that when a dualscreen apparatus with a top screen and a bottom screen is used toextract at least a portion of a gel that is formed in an aqueous mediumcomprising 0.025 N HCl and 70 mM NaCl at 37° C. from a supratherapeuticdose of the dosage forms from the medium, a first quantity of the geladheres to a lower surface of the top screen of the apparatus, and asecond quantity of the gel adheres to a upper surface of the bottomscreen of the apparatus, and the vertical thickness of the secondquantity is at least twice the vertical thickness of the first quantity.

The gels that are formed in an aqueous medium comprising 0.025 N HCl and70 mM NaCl at 37° C. from a supratherapeutic dose of the present dosageforms may also be characterized as being substantially uniformlydispersed with the medium. This means, for example, that the gel that isformed within the medium does not include a greater concentration of gelwithin any particular portion of the medium, such as within the upperportion or within the lower portion of the medium. In other words, theconcentration of gel within the medium is substantially homogenous uponvisual inspection within all portions of the medium, including withinthe upper portion of the medium and within the lower portion of themedium, respectively. A gel that is substantially uniformly dispersedwithin the medium in which it is formed may also be characterized by anabsence of portions of gel that are interspersed with portions of mediumthat do not contain gel. This can be described as the condition whereinvisually readily apparent clumps of gel are suspended in the medium. Asdescribed below, FIG. 9 illustrates the characteristic of a gel formedfrom dosage forms as disclosed herein of being substantially uniformlydispersed.

The above-described characteristics are indicative of the fact that thegels that are formed from the present dosage forms in a medium asdescribed herein are thick and viscous, with a uniform dispersion withinthe medium. These attributes, in turn, enhance the ability of thepresent dosage forms to resist uptake by or injection from a needle of ahypodermic syringe when combined with a solvent in supratherapeuticdoses, and also or alternatively to reduce the overall amount of drugthat is extractable with a solvent by entrapping the drug in a gelmatrix.

A dosage form as described can also include any of various known andconventional pharmaceutical excipients that may be useful to achievedesired processing and performance properties of an immediate releasedosage form. These excipients may include disintegrants, fillers,binders, lubricants, glidants, and coloring agents, and can be includedin core-shell particles or in a matrix (e.g., compressed matrix) of atablet or capsule. A more detailed description of pharmaceuticalexcipients that may also be included in the tablets of the presentinvention can be found in The Handbook of Pharmaceutical Excipients, 5thed. (2006). As noted above, one or more of these excipients, such as thebinder, filler, or both, may contribute to abuse deterrence in a mannerto compromise abuse practices wherein an abuser crushes, grinds, orotherwise forms the dosage form into a ground powder that might beabused by nasal insufflation, or from which active pharmaceutical agentcan be easily accessed and removed such as by dissolution or extractionusing a solvent.

Examples of fillers that may be useful in an immediate release dosageform as described include lactose, starch, dextrose, sucrose, fructose,maltose, mannitol, sorbitol, kaolin, microcrystalline cellulose,powdered cellulose, calcium sulfate, calcium phosphate, dicalciumphosphate, lactitol or any combination of the foregoing. As compared tonon-filler ingredients such as gelling polymers, a filler will have amolecular weight that does not result in a substantial viscosityincrease or formation of a gel as described herein for a gellingpolymer, if combined with a solvent such as water.

A filler may be present in any portion of a dosage form as described,including a core-shell particle; the filler may be present in a core, ina layer containing an active pharmaceutical ingredient that is disposedon the core, in a solvent resistant film, in the matrix, or in two ormore of these portions of the dosage form. The filler may be present atany one or more of these portions of a dosage form in an amount toprovide desired processing or functional properties of a portion of thedosage form and of the entire dosage form. The amount of total filler ina dosage form can also be as desired to provide desired functionality,including an immediate release profile, for example, in an amount ofgreater than 0 to 80, 5 to 50, 5 to 40, 10 to 30, 12 to 25, or 12 to 15weight percent, or in an amount of about 2, 4, 5, 7, 9, 10, 12, 13, 14,15, 16, 17, 18, 19, 20, 25, 30, 35, or 40 weight percent filler basedupon the total weight of the dosage form.

Examples of binders that may be included in a dosage form as describedherein include polymeric material such as alginic acid, sodiumcarboxymethylcellulose, microcrystalline cellulose, dextrin,ethylcellulose, gelatin, starch, pregelatinized starch, polyvinylalcohol, polyethylene oxide, polyvinylpyrrolidone, polyacrylamides,polyvinyloxoazolidone, polyvinylalcohols, methylcellulose, hydroxypropylcellulose, hydroxymethyl cellulose and any combination of two or more ofthese. A binder may be a water-soluble material. As compared tonon-binder ingredients such as a gelling polymer, a binder is of amolecular weight that does not result in formation of a gel or a highlyviscous composition upon combining with a small volume of water. Abinder can exhibit a relatively low molecular weight as compared to agelling polymer, and a relatively lower viscosity (e.g., when measuredin a 2% aqueous solution). Polymer useful as a binder may typically havea molecular weight of less than 50,000, e.g., less than 30,000, or lessthan 10,000.

A binder may be present in any portion of the present dosage forms,including in a core or a film or coating of a core-shell particle, or aspart of an excipient mixture to contain or bind core-shells particles ina dosage form, i.e., within the matrix of a dosage form as describedherein. Filler may be included in a core of a core-shell particle incombination with active pharmaceutical ingredient, gelling polymer orboth; as part of an active pharmaceutical layer located over a core oranother layer of a core-shell particle; as part of a solvent-resistantfilm; or, within an excipient mixture (matrix) useful to bind particlesinto a dosage form. A binder may be present at any one or more of theseportions of an immediate release dosage form as described, in an amountto provide desired processing or functional properties in each portionof the dosage form and of the overall dosage form. The amount of totalbinder in a dosage form can also be as desired to provide desiredfunctionality, including immediate release functionality. For example, abinder may be provided in an amount of about 0.1 to 40, 5 to 40, 10 to30, 12 to 25, or 12 to 15 weight percent, or in an amount of about 2, 4,5, 7, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, or 40weight percent binder based upon the total weight of the dosage form.

Examples of lubricants include inorganic materials such as talc (ahydrated magnesium silicate; polymers, such as, PEG 4000; fatty acids,such as stearic acid; fatty acid esters, such as glyceride esters (e.g.,glyceryl monostearate, glyceryl tribehenate, and glyceryl dibehenate);sugar esters (e.g., sorbitan monostearate and sucrose monopalmitate);glyceryl dibehenate (Compritol® 888 ATO); and metal salts of fatty acids(e.g., magnesium stearate, calcium stearate, and zinc stearate).Accordingly, commonly used lubricants include talc, glycerylmonostearates, calcium stearate, magnesium stearate, stearic acid,glyceryl behenate, polyethylene glycol, poloxamer and combinations ofthe foregoing. A lubricant may be included in an immediate releasedosage form as described, in any useful amount, such as an amount ofabout 0.1 to 10 weight percent lubricant based on a total weight of adosage form, e.g., from 0.2 to 7, 0.3 to 5, 0.5 to 3, 0.7 to 2, or 0.9to 1.5 weight percent, or in an amount of about 0.1, 0.2, 0.3, 0.4, 0.5,0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, or 5 weight percent, based on the totalweight of the dosage form.

Examples of glidants include colloidal silicon dioxide, untreated fumedsilica (e.g., as available under the trade name Cab-O-Sil®), andcrystalline or fused quartz. Glidant may be included in an immediaterelease dosage form as described, in any useful amount. For example, aglidant may be included in an amount of 0.05 to 5, 0.08 to 3, 0.1 to 2,0.15 to 1.5, 0.15 to 1, or 0.2 to 0.5 weight percent, or in an amount ofabout 0.01, 0.03, 0.05, 0.1, 0.13, 0.15, 0.17, 0.2, 0.22, 0.25, 0.27,0.3, 0.35, 0.4, 0.5, 0.7, 0.9, 1.0, 1.2, 1.4, 1.5, 1.6, 1.8, or 2percent by weight, based on the total weight of the dosage form.

Examples of coloring agents include FD&C-type dyes and lakes, fruit andvegetable extracts, titanium dioxide, iron oxides and mixtures thereof.A coloring agent may be incorporated into a dosage form by blending(e.g., co-milling and blending) the coloring agent with any otheringredient. Alternately, coloring agent may be applied to an outersurface of a dosage form.

Esketamine, alone or in combination with one or more other activepharmaceutical ingredients, are included in the immediate release dosageforms as described herein. The esketamine may be present in its freebase form or as a salt. An exemplary esketamine salt is esketaminehydrochloride.

With abuse deterrent features as described herein, some being operativebased on specific structural or compositional features of a core-shellparticle, the esketamine can be located in the dosage form at a locationto cause the API to be subject to abuse deterrent features of thecore-shell particles, e.g., at a core or inner layer of a core-shellparticle.

The amount of esketamine in the dosage forms disclosed herein can be anyuseful amount, as is known and as may be found in relevant literature.For example, typical therapeutic amounts of esketamine are 5 mg, 10 mg,20 mg, 30 mg, 40 mg. 50 mg, 60 mg, 70 mg. 80 mg, 90 mg, or 100 mg.Often, when processed into a suitable immediate release dosage form, theesketamine can be present in such dosage form in an amount normallyprescribed, typically 0.5 to 25 percent on a dry weight basis, based onthe total weight of the dosage form. In other embodiments, a dosage formcontains any appropriate amount of esketamine to provide a therapeuticeffect. When present in the core-shell particles of the dosage forms,the amount of esketamine in a core-shell particle may be about 10 toabout 40% by weight, based on the total weight of the core-shellparticle. For example, the esketamine may be present in an amount ofabout 10 to 35, 12 to 35, or 15 to 35 weight percent, or in an amount ofabout 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 weight percent, based on thetotal weight of the core-shell particle.

The presently disclosed dosage forms can optionally include one or moreadditional active pharmaceutical ingredients of a type that is notcommonly susceptible to abuse. These additional APIs may be any suitableor desired API, such as those in the class of non-steroidal analgesicdrugs. The expression “non-steroidal analgesic drugs” as used hereinrefers to drugs that include those commonly referred to as non-steroidalantiinflammatory drugs, or “NSAIDS,” and acetaminophen, which isnon-steroidal, but does not act via an inflammation mechanism.Accordingly, the term “non-steroidal analgesic drugs” would includeacetaminophen, and also include NSAIDS such as aspirin, ibuprofen, andnaproxen. The present dosage forms also exhibit immediate releaseproperties with respect to these APIs that are not commonly subject toabuse. Such APIs can be present in the dosage form at any useful level,typically 0.5 to 25, e.g., 1 to 10 weight percent of the API on a dryweight basis, based on a total weight of the dosage form, e.g., at alevel of or between 5, 25, 50, 75, 100, 125, 150, 175, 200, 300, 325,500, 750 or up to or exceeding 1000 milligram (mg) per dosage form unit.As a general matter, the present dosage forms can contain an appropriateamount of an API that is not commonly subject to abuse in order toprovide a therapeutic effect that is associated with such additionalAPI.

The present dosage forms can include one or more of the described abusedeterrent features alone or in combination; e.g., one or more of gellingpolymer as part of a core-shell particle (e.g., at a core of thecore-shell particle); wax as part of a core-shell particle (e.g., at acore of the core-shell particle); binder or filler as part of acore-shell particle (e.g., at a core of the core-shell particle); a filmlayer that may optionally be a solvent-resistant film (e.g.,pH-sensitive film) as part of a core-shell layer; or gelling polymer asa component of an excipient or binder (i.e., a matrix) used to holdcore-shell particles together. With these abuse deterrent features,other types of known abuse deterrent features may not be necessary andmay be specifically excluded from the present dosage forms. Thus,certain embodiments of the described dosage forms can specificallyexclude any of the abuse deterrent features described herein.

As for additional abuse deterrent features, the present dosage forms canoptionally include a nasal irritant to discourage or prevent abuse bynasal insufflation. The nasal irritant can be a mucous membrane irritantor nasal passageway irritant that, if inhaled through a nasal passagewaywhen contained in a ground or powdered dosage form, can induce pain orirritation of the abuser’s nasal passageway tissue. Examples includesurfactants such as sodium lauryl sulfate, poloxamer, sorbitanmonoesters, and glyceryl monooleates. Certain particular embodiments ofdosage forms of the present description do not require, and canspecifically exclude, nasal irritant agents such as those describedabove.

The present dosage forms can include an emetic agent, to cause vomiting.Certain particular embodiments of dosage forms of the presentdescription do not require and can specifically exclude an emetic agent.

The present dosage forms can include an effervescent agent that acts asa deterrent to abuse by nasal insufflation. The effervescent includes anacidic component and a basic component that release a gas such as oxygenor carbon dioxide when combined in the presence of an aqueous media,such as upon nasal insufflation. See, e.g., WO 2013/077851, the entiretyof which is incorporated herein by reference. The acid source may be,for example, citric acid, tartaric acid, malic acid, maleic acid, lacticacid, glycolic acid, ascorbic acid, fumaric acid, adipic acid, succinicacid, salts thereof, and combinations thereof. The base may be, forexample, a carbonate or bicarbonate. Dosage forms of the presentdescription do not require, and can specifically exclude, aneffervescent agent in the form of an acid and a base that can combine toa gas such as oxygen or carbon dioxide.

In one exemplary embodiment, the present oral dosage forms representcompressed tablets and comprise

-   (i) a first population of core-shell particles, each of the    core-shell particles of the first population comprises a core that    includes a gelling polymer that is hydroxypropylmethycellulose and a    wax that is glyceryl behenate; an active pharmaceutical layer    surrounding the core, the active pharmaceutical layer comprising    esketamine; and at least one layer surrounding the active    pharmaceutical layer, the at least one layer comprising a    pH-sensitive film comprising Eudragit E 100; and,-   (ii) a matrix comprising a carbomer gelling polymer, and sodium    bicarbonate, wherein the carbomer gelling polymer and sodium    bicarbonate are present in said dosage form in a ratio by weight    percentage of about 2:2 based on the total weight of the dosage    form, and optionally one or more of a disintegrant, a filler, or a    binder;

wherein the dosage form exhibits an immediate release profile of theesketamine when administered to a human in therapeutic doses, and anextended release profile of the esketamine when administered to a humanin supratherapeutic doses.

In a further embodiment, the present oral dosage forms representcompressed tablets and comprise

-   (i) a first population of core-shell particles, each of the    core-shell particles of the first population comprises a core that    includes a gelling polymer that is hydroxypropylmethycellulose and a    wax that is glyceryl behenate; an active pharmaceutical layer    surrounding the core, the active pharmaceutical layer comprising    esketamine; and at least one layer surrounding the active    pharmaceutical layer, the at least one layer comprising a    pH-sensitive film comprising Eudragit E 100; and,-   (ii) a matrix comprising a carbomer gelling polymer, and sodium    bicarbonate, wherein the carbomer gelling polymer and sodium    bicarbonate are present in said dosage form in a ratio by weight    percentage of about 2:2 based on the total weight of the dosage    form, and optionally one or more of a disintegrant, a filler, a    glidant, a lubricant, or a binder;

wherein the dosage form exhibits an immediate release profile of theesketamine when administered to a human in therapeutic doses, and anextended release profile of the esketamine when administered to a humanin supratherapeutic doses

In a further embodiment, the present oral dosage forms representcompressed tablets and comprise

-   (i) a first population of core-shell particles, each of the    core-shell particles of the first population comprises a core that    includes a gelling polymer that is hydroxypropylmethycellulose and a    wax that is glyceryl behenate; an active pharmaceutical layer    surrounding the core, the active pharmaceutical layer comprising    esketamine and hydroxypropylmethycellulose; and at least one layer    surrounding the active pharmaceutical layer, the at least one layer    comprising a pH-sensitive film comprising Eudragit E 100 and    magnesium stearate; and,-   (ii) a matrix comprising crospovidone, mannitol, microcrystalline    cellulose, silicon dioxide, magnesium stearate, a carbomer gelling    polymer, and sodium bicarbonate, wherein the carbomer gelling    polymer and sodium bicarbonate are present in said dosage form in a    ratio by weight percentage of about 2:2 based on the total weight of    the dosage form;

wherein the dosage form exhibits an immediate release profile of theesketamine when administered to a human in therapeutic doses, and anextended release profile of the esketamine when administered to a humanin supratherapeutic doses.

In a further exemplary embodiment, the present oral dosage formsrepresent compressed tablets and comprise

-   (i) a first population of core-shell particles, each of the    core-shell particles of the first population comprises a core that    includes a gelling polymer that is hydroxypropylmethycellulose and a    wax that is glyceryl behenate; an active pharmaceutical layer    surrounding the core, the active pharmaceutical layer comprising    esketamine; and at least one layer surrounding the active    pharmaceutical layer, the at least one layer comprising a    pH-sensitive film comprising Eudragit E 100;-   (ii) a second population of core-shell particles that do not include    an active pharmaceutical layer; and,-   (iii) a matrix comprising a disintegrant, a filler, a binder, a    carbomer gelling polymer, and sodium bicarbonate, wherein the    carbomer gelling polymer and sodium bicarbonate are present in said    dosage form in a ratio by weight percentage of about 2:2 based on    the total weight of the dosage form;

wherein the dosage form exhibits an immediate release profile of theesketamine when administered to a human in therapeutic doses, and anextended release profile of the esketamine when administered to a humanin supratherapeutic doses.

In yet another embodiment, the present oral dosage forms representcompressed tablets and comprise

-   (i) a first population of core-shell particles, each of the    core-shell particles of the first population comprises a core that    includes a gelling polymer that is hydroxypropylmethycellulose and a    wax that is glyceryl behenate; an active pharmaceutical layer    surrounding the core, the active pharmaceutical layer comprising    esketamine and hydroxypropylmethycellulose; and at least one layer    surrounding the active pharmaceutical layer, the at least one layer    comprising a pH-sensitive film comprising Eudragit E 100 and    magnesium stearate;-   (ii) a second population of core-shell particles that do not include    an active pharmaceutical layer; and,-   (iii) a matrix comprising crospovidone, mannitol, microcrystalline    cellulose, silicon dioxide, magnesium stearate, a carbomer gelling    polymer, and sodium bicarbonate, wherein the carbomer gelling    polymer and sodium bicarbonate are present in said dosage form in a    ratio by weight percentage of about 2:2 based on the total weight of    the dosage form;

wherein the dosage form exhibits an immediate release profile of theesketamine when administered to a human in therapeutic doses, and anextended release profile of the esketamine when administered to a humanin supratherapeutic doses.

In still another embodiment, the present oral dosage forms representcompressed tablets and comprise

-   (i) a first population of core-shell particles, each of the    core-shell particles of the first population comprises a core that    includes a gelling polymer that is hydroxypropylmethycellulose and a    wax that is glyceryl behenate; an active pharmaceutical layer    surrounding the core, the active pharmaceutical layer comprising    esketamine and hydroxypropylmethycellulose; and at least one layer    surrounding the active pharmaceutical layer, the at least one layer    comprising a pH-sensitive film comprising Eudragit E 100 and    magnesium stearate;-   (ii) a second population of core-shell particles that do not include    an active pharmaceutical layer, wherein each of the core-shell    particles of the second population comprises a core that includes a    gelling polymer that is hydroxypropylmethycellulose and a wax that    is glyceryl behenate, and a shell that includes a pH-sensitive film    comprising Eudragit E 100 and magnesium stearate; and,-   (iii) a matrix comprising crospovidone, mannitol, microcrystalline    cellulose, silicon dioxide, magnesium stearate, a carbomer gelling    polymer, and sodium bicarbonate, wherein the carbomer gelling    polymer and sodium bicarbonate are present in said dosage form in a    ratio by weight percentage of about 2:2 based on the total weight of    the dosage form;

wherein the dosage form exhibits an immediate release profile of theesketamine when administered to a human in therapeutic doses, and anextended release profile of the esketamine when administered to a humanin supratherapeutic doses.

According to further embodiments, provided herein are abuse resistantoral dosage forms for the administration of esketamine to a subjectcomprising: (i) a first population of core-shell particles, each of thecore-shell particles of the first population comprising a core, anactive pharmaceutical layer surrounding the core, the activepharmaceutical layer comprising esketamine or a pharmaceuticallyacceptable salt thereof, and at least one layer surrounding the activepharmaceutical layer, the at least one layer comprising a pH-sensitivefilm comprising a pH-sensitive polymer that is insoluble in water at apH greater than 5; and, (ii) a matrix comprising a carbomer gellingpolymer and sodium bicarbonate, wherein the carbomer gelling polymer andsodium bicarbonate are present in a ratio by weight percentage of about2:2 based on the total weight of the dosage form; wherein the dosageform exhibits an immediate release profile of esketamine having not lessthan 90% of the esketamine released in 60 minutes, wherein the releaseprofile is evaluated by dissolution of the tablet in 300 mL of 0.1N HC1media using USP II apparatus at 50 RPM paddle speed and 37° C.; whereinthe dosage form exhibits an immediate release profile of the esketaminewhen administered to a human in therapeutic doses, and an extendedrelease profile of the esketamine when administered to a human insupratherapeutic doses, or wherein the dosage form exhibits abuseresistant properties when physically manipulated, or wherein the dosageform exhibits abuse resistant properties when physically manipulated andadministered in a manner not consistent with oral dosing, or wherein thedosage form exhibits abuse resistant properties when administered in amanner intended to result in administration of the esketamine in ahigher than therapeutic dose.

In accordance with some of these embodiments, when the dosage form isphysically manipulated by crushing to form a population of particles, arelatively low proportion of the population comprises a subpopulation ofparticles having a particle size of less than 75 µm. For example, lessthan 25, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5wt% of such particles can comprise a subpopulation of particles having aparticle size of less than 75 µm. In some embodiments, 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 27, 18, 19, or 20% of thepopulation of particles comprises a subpopulation of particles having aparticle size of less than 75 µm.

As used throughout the present disclosure, “crushing” or “crushed”refers to a sample that has been physically manipulated by mechanicalmeans thereby leading to the sample’s partial or completedisintegration, wherein the manipulation takes place for a time periodof up to about 90 seconds and wherein at the completion of themanipulation, less than 10% of the recovered sample has a particle sizeof >500 µm and, by weight, more than about 99% of the sample can berecovered.

In certain of these embodiments, when the dosage form is physicallymanipulated by crushing to form a population of particles, less than 40wt.% (e.g., 0 wt% to 39.5 wt.%, 10 wt.% to 39.5 wt.%, 10 wt% to 30 wt.%,10 wt% to 20 wt.%, about 39.5 wt.%, 39 wt.%, 38.5 wt.%, 38 wt.%, 37.5wt.%, 37 wt.%, 36.5 wt.%, 36 wt.%, or 35.5 wt.%) of the population ofparticles comprises a subpopulation of particles having a particle sizeof less than 106 µm, and wherein said subpopulation contains less than10 wt.% base equivalent (e.g., less than about 9.5 wt.%, 9 wt.%, 8.5wt.%, 8 wt.%, 7.5 wt.%, 7 wt.%, 6.5 wt.%, 6 wt.%, 5.5 wt.%, 5 wt.%) ofthe esketamine of said dosage form. In some embodiments, when the dosageform is physically manipulated by crushing to form a population ofparticles, less than 35 wt.% (e.g., less than about 34.5, 34, 33.5, 33,32.5, or 32 wt.%) comprises a subpopulation of particles having aparticle size of 212-500 µm and containing less than 70 wt.% baseequivalent (e.g., less than about 69, 68, 67, 66, 65, 64, 63, 62, 61,60, 58, 55 or 50 wt.%) of the esketamine of said dosage form. In someembodiments, when the dosage form is physically manipulated by crushingto form a population of particles, less than 30 wt.% (e.g., less thanabout 29, 28, 27, 26, 25, 24, 22 or 20 wt.%) comprises a subpopulationof particles having a particle size of 106-212 µm and wherein thesubpopulation of particles contains less than 20 wt.% base equivalent(e.g., less than about 19.5, 19, 18, 17, 16, 15, 14, 13, 12, 11, or 10wt.%) of the esketamine of said dosage form.

In certain embodiments, the present dosage forms exhibit one or more ofthe abuse resistant properties when the dosage form is physicallymanipulated by crushing and subsequently heating prior to theadministration in a manner not consistent with oral dosing or in amanner that would result in administration of the esketamine in a higherthan therapeutic dose (e.g., higher than therapeutic C_(max)), if acontrol dosage form were similarly administered. As described more fullyin the examples below, one or more of the abuse resistant properties ofthe present dosage forms remain effective to prevent successful attemptsto administer the active ingredient in a dose that is not consistentwith therapeutic use of the dosage form, even when subjected to physicalmanipulation (e.g., crushing) and subsequent heating, which otherwiserepresents a commonly used approach to defeat, for example, gellingproperties of a dosage form. In certain embodiments, the heatingcomprises subjecting the physically manipulated (e.g., crushed) dosageform to a temperature of about 200° C.-300° C. For example, the heatingmay be performed at a temperature of about 200, 210, 220, 230, 240, 250,260, 270, 280, 290, or 300° C. The heating of the physically manipulateddosage form may have a duration of at least one minute. For example, theheating may have a duration of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, or 20 minutes, or longer. The heated,physically manipulated dosage forms according to the present disclosuremay release less esketamine (base equivalent) after incubation in wateror 0.1 N HCl for up to 18 hours, as compared to the release ofesketamine from a physically manipulated dosage form control that hasnot been heated prior to incubation in water or 0.1 N HCl for up to 18hours. In some embodiments, the heated, physically manipulated dosageform releases at least 20 wt.% less esketamine, as compared to therelease of esketamine (base equivalent) from a physically manipulateddosage form control that has not been heated prior to incubation inwater or 0.1 N HCl for up to 18 hours. For example, the heated,physically manipulated dosage form may release about 20-55, 20-50,23-50, 25-45, 30-40, or 35-40 wt.% less esketamine, or about 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55 wt.% lessesketamine, as compared to the release of esketamine (base equivalent)from a physically manipulated dosage form control that has not beenheated prior to incubation in water or 0.1 N HCl for up to 18 hours.

The present dosage forms may also resist attempted abuse by physicalmanipulation (e.g., crushing and optionally wetting) followed by nasalinsufflation, which represents a further commonly used approach forattempted abuse of an active ingredient from a dosage form. Thischaracteristic is described more fully in connection with the examples,infra. With respect to certain embodiments, upon physically manipulatingthe dosage form by crushing, the physically manipulated dosage formexhibits less than 5 wt.% (e.g., less than about 4.9, 4.8, 4.7, 4.6,4.5, 4.4, 4.3, 4.2, 4.1, 4, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1,3 wt.%) the esketamine diffusion of powdered pure esketamine or apharmaceutically acceptable salt thereof, over 60 minutes across amembrane having a molecular weight cutoff of 12-14 kD from a receptorchamber containing a phosphate buffer at pH 6.4 and maintained at 37° C.In some embodiments, wherein upon physically manipulating the dosageform by crushing, the physically manipulated dosage form exhibits lessesketamine diffusion across nasal membranes of a human subject whennasally insufflated by the subject, relative to a solution of 140 mg/mlesketamine (base equivalent) in pH 4.5 citrate buffer. With respect tosome embodiments, wherein upon physically manipulating the dosage formby crushing, the physically manipulated dosage form exhibits less than5% the relative esketamine diffusion of a solution of 140 mg/mlesketamine (base equivalent) in pH 4.5 citrate buffer, over 60 minutesacross a membrane having a molecular weight cutoff of 12-14 kD from areceptor chamber containing a phosphate buffer at pH 6.4 and maintainedat 37° C. In some embodiments, wherein upon physically manipulating thedosage form by crushing, the absorption of esketamine from thephysically manipulated dosage form over 60 minutes across a membranehaving a molecular weight cutoff of 12-14 kD from a receptor chambercontaining a phosphate buffer at pH 6.4 and maintained at 37° C. is lessthan 20%, e.g., about 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7,6, 5, 4, 3, or 2%. With respect to these embodiments, the physicallymanipulated dosage form according to the present disclosure may be dryor pre-wetted prior to the aforementioned assessment of absorptionacross a membrane.

The present disclosure also provides oral tablets for the administrationof esketamine to a subject comprising: a total weight of not less than800 mg (e.g., not less than about 800, 816, 833, 851, 870, 889, 909,930, 952, 976, 1000, 1026, 1053, 1081, 1111, 1143, 1176, 1212, 1250,1290, 1333 mg), and having 40 mg of esketamine (base equivalent), theesketamine (base equivalent) representing less than 5.0% (e.g., lessthan about 4.9, 4.8, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4.0, 3.9, 3.8,3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1, 3.0%) by weight of the total weightof the tablet. In other aspects, the disclosure provides oral tabletsfor the administration of esketamine to a subject comprising: a totalweight of not less than 571 mg (e.g., not less than about 571, 588, 606,625, 667, 690, 714, 741, 769, 800, 833, 870, 909, 952, 1000, 1053, 1111,1176, 1250, 1333 mg),, and having 20 mg of esketamine (base equivalent),the esketamine (base equivalent) representing less than 3.5% (e.g., lessthan about 3.5, 3.4, 3.3, 3.2, 3.1, 3.0. 2.9.2.8, 2.7, 2.6, 2.5, 2.4,2.3, 2.2, 2.1, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5%) by weight of the totalweight of the tablet. In these aspects, the tablet exhibits an immediaterelease profile of esketamine, having not less than 90% of theesketamine released in 60 minutes, and wherein the release profile isevaluated by dissolution of the tablet in 300 mL of 0.1N HC1 media usingUSP II apparatus at 50 RPM paddle speed and 37° C.; and wherein thetablet exhibits an immediate release profile of the esketamine whenadministered to a human in therapeutic doses, and an extended releaseprofile of the esketamine when administered to a human insupratherapeutic doses, or wherein the tablet exhibits abuse resistantproperties when physically manipulated, or wherein the tablet exhibitsabuse resistant properties when physically manipulated and administeredin a manner not consistent with oral dosing, or wherein the tabletexhibits abuse resistant properties when administered in a mannerintended to result in administration of the esketamine in a higher thantherapeutic dose.

Also disclosed herein are methods for reducing the potential for abuseby a human of an active pharmaceutical ingredient comprising esketamineby simultaneous oral ingestion of multiple dosage units comprising theactive pharmaceutical ingredient, comprising providing to the human adosage form according to any of the embodiments described herein.

The present disclosure also provides methods for reducing the potentialfor abuse by nasal insufflation by a human of an active pharmaceuticalingredient comprising esketamine, comprising providing to the human adosage form according to any of the embodiments described herein.

Also provided are methods for treating or preventing pain or discomfortin a subject in need thereof by administering to the subject a dosageform according to any of the embodiments described herein. Likewise, thepresent disclosure provides methods for treating depression in a subjectin need thereof by administering to the subject a dosage form accordingto any of the embodiments described herein.

Impurities can be present in the active pharmaceutical ingredient (API)or in the pharmaceutical dosage form, for example, in tablets comprisingthe API and pharmaceutically acceptable excipients. In the case ofimpurities found in the pharmaceutical dosage form that do not arisefrom having been present in the corresponding API, those impurities maybe the result of one or more excipients reacting with esketaminehydrochloride. Such reactions may give rise to esketamine hydrochloridedegradation and/or the formation of esketamine by-products. In someinstances, degradation, side product formation, by-product formation,and/or adjunct reagent formation occurs only after storage, for example,long-term storage, or after exposure to accelerated stability studies.

Generally, side products, by-products, and adjunct reagents (singularly“impurity” or collectively “impurities”) are defined spectroscopicallyand/or with another physical method, and then associated with a peakposition, such as that in a chromatogram or a spot on a thin layerchromatography (TLC) plate. (Strobel, H. A.; Heineman, W. R., ChemicalInstrumentation: A systematic Approach, 3^(rd) ed. (Wiley & Sons: NewYork 1989) p. 953.) Thereafter, the impurity can be identified by itsposition in the chromatogram where the position in a chromatogram isconventionally measured in minutes between injection of the sample onthe column and elution of the particular component through the detector.The retention time can vary based upon the condition of theinstrumentation, as well as many other factors. To mitigate the effectssuch variations have upon accurate identification of an impurity,practitioners use the “Relative retention time,” (RRT) to identifyimpurities. (Strobel p. 922) The RRT of an impurity is defined as theretention time of the impurity divided by the retention time of areference marker. It may be advantageous to select a compound other thanthe API that is added to the mixture in an amount sufficiently large tobe detectable and sufficiently low as not to saturate the column and touse that compound as the reference marker for determination of the RRT.

A reference standard is a compound in a relatively pure state, used toquantify the amount of the compound in an unknown mixture. A referencestandard can be used as either an external standard or as an internalstandard. An external standard is employed when a solution of a knownconcentration of the reference standard and an unknown mixture areanalyzed using the same technique. The amount of the compound in themixture can be determined by comparing the magnitude of the detectorresponses. An internal standard is employed when an unknown mixturecontains a detectable amount of the reference standard compound withoutaddition of the reference standard. The amount of internal standard isdetermined by preparing at least two samples by adding known anddiffering amounts of the internal standard. The proportion of thedetector response due to the reference standard present in the mixturecan be determined by plotting the detector response attained for each ofthe samples against the amount of the reference standard added to eachof the samples and extrapolating the plot to zero.

The present disclosure provides immediate release tablets comprisingesketamine or a pharmaceutically acceptable salt thereof, a pH adjusterin an amount of no more than about 2 wt% and2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one inamount in an amount of no more than about 5 wt% after storage inaccelerated conditions for at least 6 months.

In one embodiment, the pH adjuster is in the dosage form in an amount ofno more than 2 percent by weight. In one embodiment, the pH adjuster isin the dosage form in an amount of no more than 2 percent, no more than1.9 percent, no more than 1.8 percent, no more than 1.7 percent, no morethan 1.6 percent, no more than 1.5 percent, no more than 1.4 percent, nomore than 1.3 percent, no more than 1.2 percent, no more than 1.1percent, no more than 1 percent, no more than 0.9 percent, no more than0.8 percent, no more than 0.7 percent, no more than 0.6 percent, no morethan 0.6 percent, no more than 0.5 percent, no more than 0.4 percent, nomore than 0.3 percent, no more than 0.2 percent, or no more than 0.1percent by weight. In one embodiment, the present dosage form comprisesa pH adjuster in an amount that is less than 0.1 percent by weight. Inone embodiment, the present dosage form does not comprise a pH adjuster.

In one embodiment, the pH adjuster is in the form of a base. Suitableagents that can act as a pH adjuster include, for example, phosphatebuffering agents such as, disodium hydrogen phosphate, sodium dihydrogenphosphate and the equivalent potassium salts; carbonate or bicarbonatesalts, such as sodium bicarbonate, sodium carbonate, potassiumbicarbonate, potassium carbonate, magnesium carbonate and calciumcarbonate; hydroxide bases such as, sodium hydroxide, potassiumhydroxide, ammonium hydroxide; and amine bases such as, triethanolamine,tromethamine, aminomethyl propanol, and tetrahydroxypropylethylenediamine. In one embodiment, the pH adjuster is sodiumbicarbonate.

In one embodiment, the2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one in thedosage form is present in an amount of no more than 5 percent by weight.In one embodiment, the2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one in thedosage form is in an amount of no more than 5 percent, no more than 4.9percent, no more than 4.8 percent, no more than 4.7 percent, no morethan 4.6 percent, no more than 4.5 percent, no more than 4.4 percent, nomore than 4.3 percent, no more than 4.2 percent, no more than 4.1percent, no more than 4 percent, no more than 3.9 percent, no more than3.8 percent, no more than 3.7 percent, no more than 3.6 percent, no morethan 3.5 percent, no more than 3.4 percent, no more than 3.3 percent, nomore than 3.2 percent, no more than 3.1 percent, no more than 3 percent,no more than 2.9 percent, no more than 2.8 percent, no more than 2.7percent, no more than 2.6 percent, no more than 2.5 percent, no morethan 2.4 percent, no more than 2.3 percent, no more than 2.2 percent, nomore than 2.1 percent, no more than 2 percent, no more than 1.9 percent,no more than 1.8 percent, no more than 1.7 percent, no more than 1.6percent, no more than 1.5 percent, no more than 1.4 percent, no morethan 1.3 percent, no more than 1.2 percent, no more than 1.1 percent, nomore than 1 percent, no more than 0.9 percent, no more than 0.8 percent,no more than 0.7 percent, no more than 0.6 percent, no more than 0.5percent, no more than 0.45 percent, no more than 0.4 percent, no morethan 0.35 percent, no more than 0.3 percent, no more than 0.25 percent,no more than 0.2 percent, no more than 0.19 percent, no more than 0.18percent, no more than 0.17 percent, no more than 0.16 percent, no morethan 0.15 percent, no more than 0.14 percent, no more than 0.13 percent,no more than 0.12 percent, no more than 0.11 percent, no more than 0.1percent, no more than 0.09 percent, no more than 0.08 percent, no morethan 0.07 percent, no more than 0.06 percent, no more than 0.05 percent,no more than 0.04 percent, no more than 0.03 percent, no more than 0.02percent, or no more than 0.01 percent by weight. In one embodiment, thepresent dosage form is substantially free of2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one.

In one embodiment, the present dosage form does not comprise by weightany 2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one,namely the present dosage form comprises no detectable2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one byweight, as determined by HPLC, using UV detection at 215 nm. As usedthroughout the present disclosure, “substantially free” refers to thepresent dosage form having less than 0.01 percent by weight of aparticular ingredient or excipient as determined by HPLC, using UVdetection at 215 nm.

As used throughout the present disclosure, “accelerated conditions”refers to 40° C. ± 2° C. and 75% ± 5% relative humidity (RH). In oneembodiment, the storage in accelerated conditions is at 40° C. ± 2° C.and 75% ± 5% RH. In one embodiment, the storage is at 40° C. and 75% RH.In one embodiment, the storage is for at least 6 months. In oneembodiment, the storage is for at least 6, at least 7, at least 8, atleast 9, at least 10, at least 11, at least 12, at least 13, at least14, at least 15, at least 16, at least 17, at least 18, at least 19, atleast 20, at least 21, at least 22, at least 23, at least 24, at least25, at least 26, at least 27, at least 28, at least 29, at least 30, atleast 31, at least 32, at least 33, at least 34, at least 35, or atleast 36 months.

The amount of esketamine in the dosage forms can be any useful amount,as is known and as may be found in relevant literature. For example,typical therapeutic amounts of esketamine are 5 mg, 10 mg, 20 mg, 30 mg,40 mg. 50 mg, 60 mg, 70 mg. 80 mg, 90 mg, or 100 mg. In one embodiment,the amount of esketamine in the dosage form comprises between 5 and 100mg of esketamine (base equivalent) or pharmaceutically acceptable saltthereof. In one embodiment, the amount of esketamine in the dosage formcomprises 20 mg of esketamine (base equivalent) or pharmaceuticallyacceptable salt thereof. In one embodiment, the amount of esketamine inthe dosage form 40 mg of esketamine (base equivalent) orpharmaceutically acceptable salt thereof.

The present disclosure provides immediate release tablets comprisingesketamine or a pharmaceutically acceptable salt thereof, a pH adjusterin an amount of no more than about 2 wt%, a polymer, and2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one inamount that is no more than about 5 wt% after storage in acceleratedconditions for at least 6 months.

In one embodiment, the present dosage form comprises a polymer. In oneembodiment, the present dosage form comprises more than one polymers. Inone embodiment, the one or more polymers are gelling polymers (e.g.natural starches, synthetic starches, natural celluloses, syntheticcelluloses, acrylates, polyalkylene oxides, carbomers and combinationsthereof) and can be independently selected from ethylcellulose,cellulose acetate, cellulose acetate propionate, cellulose acetatebutyrate, cellulose acetate phthalate, cellulose triacetate, celluloseether, cellulose ester, cellulose ester ether, cellulose, hydroxypropylmethyl cellulose, hydroxy methyl cellulose, methyl cellulose,hydroxyethylmethyl cellulose, sodium carboxymethyl cellulose, a carbomerpolymer, polyethylene oxide, and combinations thereof. In oneembodiment, the one or more polymers are pH-sensitive polymers. In oneembodiment, the one or more pH-sensitive polymers is a copolymer ofdimethyl aminoethyl methacrylate, butyl methacrylate, and methylmethacrylate monomers.

In one embodiment, the one or more polymers are C1 moiety donatingpolymers. As used throughout the present disclosure, “C1 moiety” refersto a chemical fragment comprising only one Carbon atom (e.g. methyl,methylene). As used throughout the present disclosure, a “C1 moietydonating polymer” is a polymer capable of transferring from itself toanother substance a C1 moiety.

In one embodiment, the esketamine or a pharmaceutically acceptable saltthereof, is in contact with a polymer. As used throughout the presentdisclosure, “in contact with” refers to two or more substances that areclose enough to interact with each other. In one embodiment, the contactmay be direct contact or physical contact, where there is generally nomeasurable space or distance between the contact points of the twosubstances. In one embodiment, the contact may be indirect contact, ornon-physical contact, where there is a measurable space or distancebetween the contact points of the two substances.

In one embodiment, the ratio, by weight, of polymer in contact withesketamine or pharmaceutically acceptable salt thereof, is between about2 and about 15.8 to 1. In one embodiment, the ratio, by weight, ofpolymer in contact with esketamine is between about 2 and about 15.8 to1 (i.e., ~2 to ~ 15.8:1). In one embodiment, the ratio, by weight, ofpolymer in contact with esketamine is about 2, about 2.1, about 2.2,about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about2.9, about 2, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5,about 2.6, about 2.7, about 2.8, about 2.9, about 3, about 3.1, about3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8,about 3.9, about 4, about 4.1, about 4.2, about 4.3, about 4.4, about4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5, about 5.1,about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about5.8, about 5.9, about 6, about 6.1, about 6.2, about 6.3, about 6.4,about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7, about7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7,about 7.8, about 7.9, about 8, about 8.1, about 8.2, about 8.3, about8.4, about 8.5, about 8.6, about 8.7, about 8.8, about 8.9, about 9,about 9.1, about 9.2, about 9.3, about 9.4, about 9.5, about 9.6, about9.7, about 9.8, about 9.9, about 10, about 10.1, about 10.2, about 10.3,about 10.4, about 10.5, about 10.6, about 10.7, about 10.8, about 10.9,about 11, about 11.1, about 11.2, about 11.3, about 11.4, about 11.5,about 11.6, about 11.7, about 11.8, about 11.9, about 12, about 12.1,about 12.2, about 12.3, about 12.4, about 12.5, about 12.6, about 12.7,about 12.8, about 12.9, about 13, about 13.1, about 13.2, about 13.3,about 13.4, about 13.5, about 13.6, about 13.7, about 13.8, about 13.9,about 14, about 14.1, about 14.2, about 14.3, about 14.4, about 14.5,about 14.6, about 14.7, about 14.8, about 14.9, about 15, about 15.1,about 15.2, about 15.3, about 15.4, about 15.5, about 15.6, about 15.7or about 15.8 to 1.

In one embodiment, the ratio, by weight, of polymer in contact withesketamine or pharmaceutically acceptable salt thereof, is at leastabout 2 to 1. In one embodiment, the ratio, by weight, of polymer incontact with esketamine is at least about 2, at least about 2.1, atleast about 2.2, at least about 2.3, at least about 2.4, at least about2.5, at least about 2.6, at least about 2.7, at least about 2.8, atleast about 2.9, at least about 2, at least about 2.1, at least about2.2, at least about 2.3, at least about 2.4, at least about 2.5, atleast about 2.6, at least about 2.7, at least about 2.8, at least about2.9, at least about 3, at least about 3.1, at least about 3.2, at leastabout 3.3, at least about 3.4, at least about 3.5, at least about 3.6,at least about 3.7, at least about 3.8, at least about 3.9, at leastabout 4, at least about 4.1, at least about 4.2, at least about 4.3, atleast about 4.4, at least about 4.5, at least about 4.6, at least about4.7, at least about 4.8, at least about 4.9, at least about 5, at leastabout 5.1, at least about 5.2, at least about 5.3, at least about 5.4,at least about 5.5, at least about 5.6, at least about 5.7, at leastabout 5.8, at least about 5.9, at least about 6, at least about 6.1, atleast about 6.2, at least about 6.3, at least about 6.4, at least about6.5, at least about 6.6, at least about 6.7, at least about 6.8, atleast about 6.9, at least about 7, at least about 7.1, at least about7.2, at least about 7.3, at least about 7.4, at least about 7.5, atleast about 7.6, at least about 7.7, at least about 7.8, at least about7.9, at least about 8, at least about 8.1, at least about 8.2, at leastabout 8.3, at least about 8.4, at least about 8.5, at least about 8.6,at least about 8.7, at least about 8.8, at least about 8.9, at leastabout 9, at least about 9.1, at least about 9.2, at least about 9.3, atleast about 9.4, at least about 9.5, at least about 9.6, at least about9.7, at least about 9.8, at least about 9.9, at least about 10, at leastabout 10.1, at least about 10.2, at least about 10.3, at least about10.4, at least about 10.5, at least about 10.6, at least about 10.7, atleast about 10.8, at least about 10.9, at least about 11, at least about11.1, at least about 11.2, at least about 11.3, at least about 11.4, atleast about 11.5, at least about 11.6, at least about 11.7, at leastabout 11.8, at least about 11.9, at least about 12, at least about 12.1,at least about 12.2, at least about 12.3, at least about 12.4, at leastabout 12.5, at least about 12.6, at least about 12.7, at least about12.8, at least about 12.9, at least about 13, at least about 13.1, atleast about 13.2, at least about 13.3, at least about 13.4, at leastabout 13.5, at least about 13.6, at least about 13.7, at least about13.8, at least about 13.9, at least about 14, at least about 14.1, atleast about 14.2, at least about 14.3, at least about 14.4, at leastabout 14.5, at least about 14.6, at least about 14.7, at least about14.8, at least about 14.9, at least about 15, at least about 15.1, atleast about 15.2, at least about 15.3, at least about 15.4, at leastabout 15.5, at least about 15.6 or at least about 15.7 to 1.

In one embodiment, the weight percentage ratio of polymer to esketamineis less than 2.6 to 1. In one embodiment, the weight percentage ratio ofpolymer to esketamine is less than 2.6, less than 2.5, less than 2.4,less than 2.3, less than 2.2, less than 2.1, less than 2, less than 1.9,less than 1.8, less than 1.7, less than 1.6, less than 1.5, less than1.4, less than 1.3, less than 1.2, less than 1.1, less than 1, less than0.9, less than 0.8, less than 0.7, less than 0.6, less than 0.5, lessthan 0.4, less than 0.3, less than 0.2 or less than 0.1 to 1. In oneembodiment, the weight percentage ratio of polymer to esketamine (baseequivalent) is 0.75 to 1. In one embodiment, the weight percentage ratioof polymer to pharmaceutically acceptable salt of esketamine is 0.65 to1.

In one embodiment, the ratio, by weight of polymer is to esketamine(base equivalent). In another embodiment, the ratio, by weight ofpolymer is to a pharmaceutically acceptable salt of esketamine. In oneembodiment, the ratio, by weight, is of any polymer in contact with theesketamine or pharmaceutically acceptable salt thereof. In anotherembodiment, the ratio, by weight, is of the total polymer in contactwith the esketamine or pharmaceutically acceptable salt.

The present disclosure also provides methods of manufacturing animmediate release tablet comprising esketamine or a pharmaceuticallyacceptable salt thereof and a pH adjuster in an amount of no more thanabout 2 wt%. In one embodiment, the method comprises wet millingexcipients. In one embodiment, the method comprises dry millingexcipients. In one embodiment, the method comprises wet followed by drymilling excipients. In one embodiment, the immediate release tabletmanufactured according to the method comprises2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one in anamount that is no more than about 5 wt% after storage in acceleratedconditions for at least 6 months.

The present disclosure also provides for methods of treating depressioncomprising orally administering to a subject in need thereof, animmediate release tablet comprising esketamine or a pharmaceuticallyacceptable salt thereof, a pH adjuster in an amount of no more thanabout 2 wt% and2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one inamount that is no more than about 5 wt% after storage in acceleratedconditions for at least 6 months. In one embodiment, the present dosageform comprises between 5 and 100 mg of esketamine or pharmaceuticallyacceptable salt thereof. In one embodiment, the present dosage formcomprises 5 mg, 10 mg, 20 mg, 30 mg, 40 mg. 50 mg, 60 mg, 70 mg. 80 mg,90 mg, or 100 mg of esketamine or pharmaceutically acceptable saltthereof. In one embodiment, the present dosage form comprises between 5and 100 mg of esketamine (base equivalent) or pharmaceuticallyacceptable salt thereof. In one embodiment, the present dosage formcomprises 20 mg of esketamine (base equivalent) or pharmaceuticallyacceptable salt thereof. In one embodiment, the present dosage formcomprises 40 mg of esketamine (base equivalent) or pharmaceuticallyacceptable salt thereof.

The present disclosure also provides for immediate release oral tabletscomprising core shell particles, comprising

-   a) a core surrounded by a first layer comprising esketamine and    pharmaceutically acceptable salts thereof and a second layer    comprising a pH-sensitive polymer that is soluble in an aqueous    environment at a pH below 5, wherein the first layer is at least    partially surrounded by the second layer;-   b) no more than 2 wt% of a pH adjuster; and-   c) no more than about 5 wt% of    2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one    after storage in accelerated conditions for at least 6 months.

In one embodiment, the core comprises a gelling polymer (e.g. naturalstarches, synthetic starches, natural celluloses, synthetic celluloses,acrylates, polyalkylene oxides, carbomers and combinations thereof). Inone embodiment, the core comprises one or more gelling polymers. In oneembodiment, the gelling polymer can be independently selected fromethylcellulose, cellulose acetate, cellulose acetate propionate,cellulose acetate butyrate, cellulose acetate phthalate, cellulosetriacetate, cellulose ether, cellulose ester, cellulose ester ether,cellulose, hydroxypropyl methyl cellulose, hydroxy methyl cellulose,methyl cellulose, hydroxyethylmethyl cellulose, sodium carboxymethylcellulose, a carbomer polymer, polyethylene oxide, and combinationsthereof.

In one embodiment, the first layer comprises esketamine orpharmaceutically acceptable salts thereof and a polymer. In oneembodiment, the polymer is a gelling polymer. In one embodiment, thepolymer is hypromellose (HPMC).

In one embodiment, the one or more pH-sensitive polymers is a copolymerof dimethyl aminoethyl methacrylate, butyl methacrylate, and methylmethacrylate monomers.

The present disclosure provides for an isolated compound of the formula:2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one. Thedisclosure also provides a composition comprising2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one whereinthe composition is free of esketamine and to a composition comprising2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one in anamount of at least 0.2 wt% and a carrier.

The present disclosure also provides a pharmaceutical compositioncomprising a granulate of a mixture of: a) esketamine hydrochloride; b)at least one pharmaceutically acceptable carrier; and c) less than 5 wt%of 2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one.

The present disclosure also provides a process for preparing animmediate release tablet comprising esketamine hydrochloride and apharmaceutically acceptable carrier, wherein the tablet comprises lessthan 5 wt % of2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one,comprising:

-   a. obtaining esketamine hydrochloride drug substance;-   b. determining the total amount of    2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one    present in the esketamine hydrochloride drug substance; and-   c. including in the preparation of the tablet the esketamine    hydrochloride drug substance determined to have less than about 5    wt% of    2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one.

The present disclosure also provides a process for validating a batch ofimmediate release tablets containing esketamine hydrochloride and atleast one pharmaceutically acceptable carrier for distributioncomprising:

-   a. determining whether the total amount of    2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one in    a sample of the batch after stability testing is less than about 5    wt% of    2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one;    and-   b. validating the batch for distribution that has been determined to    have less than about 5 wt% of    2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one.

As used throughout the present disclosure, “stability testing” shallinclude testing at accelerated conditions for at least 6 months.

The present disclosure provides a compound of the following structuralformula:

The chemical name of this compound is:2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one. Asused throughout the present disclosure,“2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one”refers to both racemic and enantiomerically enriched, e.g.enantiomerically pure, forms of the compound. In one embodiment, thecompound is racemic2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one. In oneembodiment, the compound is enantiomerically enriched in one enantiomer.In one embodiment, the compound is enriched in the S enantiomer. Inanother embodiment, the compound is enriched in the R enantiomer.

The present disclosure also provides an isolated compound of formula:2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one and toa composition comprising a compound of formula:2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one whereinthe composition is free of esketamine hydrochloride.

The present disclosure also provides a composition comprising2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one in anamount of at least 0.2 wt% and a carrier. In one embodiment, thecomposition comprises at least 1.5 wt% of2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one, basedon the weight of the composition.

In another embodiment, the composition comprises at least 50 wt% of2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one. Inanother embodiment, the composition comprises from more than 0 to 99.5wt% by weight of esketamine hydrochloride. In another embodiment, thecomposition comprises from more than 0 to 95 wt% by weight of esketaminehydrochloride.

In another embodiment, the composition is a pharmaceutical compositionand the carrier is a pharmaceutically acceptable carrier. In oneembodiment of the pharmaceutical composition,2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one ispresent in an amount between 0.01 wt% and 5.0 wt% in the composition. Inanother embodiment of the pharmaceutical composition,2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one ispresent in an amount between 0.01 wt% and 0.5 wt% in the composition. Inanother embodiment of the pharmaceutical composition,2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one ispresent in an amount between 0.01 wt% and 0.2 wt% in the composition. Inanother embodiment of the pharmaceutical composition, the2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one ispresent in an amount between 0.01 wt% and 0.1 wt% in the composition.

The present disclosure also provides a pharmaceutical compositioncomprising a granulate of a mixture of: a) esketamine hydrochloride; b)at least one pharmaceutically acceptable carrier; and c) less than 5 wt%of 2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one. Inone embodiment of the pharmaceutical composition,2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one ispresent in an amount less than 0.5 wt%. In one embodiment of thepharmaceutical composition,2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one ispresent in an amount less than 0.1 wt%.

In one embodiment of the pharmaceutical composition, the granulate is aproduct of wet granulation. In one embodiment of the pharmaceuticalcomposition, the granulate is a milled granulate. In one embodiment ofthe pharmaceutical composition, the granulate is both wet granulated andmilled. In one embodiment of the pharmaceutical composition, thegranulate is both wet and dry milled.

In one embodiment, the pharmaceutical composition further comprises nomore than 2 wt% of a pH adjuster. In one embodiment, the pharmaceuticalcomposition is in the form of an immediate release tablet.

In one embodiment of the pharmaceutical composition, the tabletcomprises, by weight, between 1% and 4% esketamine hydrochloride, nomore than 2% of a pH adjuster and no more than 5% of2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one.

The present disclosure also provides a sealed package comprising thecomposition described herein or the pharmaceutical composition describedherein. In one embodiment of the sealed package, a net increase of thetotal content of2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one in thepharmaceutical composition is 5 wt% or less after storage of the sealedpackage at accelerated conditions for at least 6 months. In oneembodiment, the net increase is 0.5 wt% or less after storage ataccelerated conditions for at least 6 months. In one embodiment, the netincrease is 0.1 wt% or less after storage at accelerated conditions forat least 6 months. In one embodiment, the net increase is less than 0.1wt% after storage at accelerated conditions for at least 6 months.

In one embodiment, the sealed package comprises the pharmaceuticalcomposition described herein, wherein the pharmaceutical compositioncontains less than 5 wt% of2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one afterstorage of the sealed package at accelerated conditions for at least 6months. In one embodiment, the pharmaceutical composition contains 0.5wt% of 2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-oneor less after storage at accelerated conditions for at least 6 months.In one embodiment, the pharmaceutical composition contains 0.1 wt% of2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one or lessafter storage at accelerated conditions for at least 6 months. In oneembodiment, the pharmaceutical composition contains less than 0.1 wt% of2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one afterstorage at accelerated conditions for at least 6 months.

In one embodiment of the sealed package, the pharmaceutical compositionfurther comprises2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one in anamount of 1.0 wt%, or below, in the pharmaceutical composition. Inanother embodiment of the sealed package,2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one ispresent in the pharmaceutical composition in an amount of less than 0.1wt%. In another embodiment of the sealed package, the pharmaceuticalcomposition contains less than 1.0 wt% of2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one afterstorage of the sealed package at accelerated conditions for at least 6months. In one embodiment of the sealed package, a net increase of thetotal content of2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one in thepharmaceutical composition is 5 wt% or less after storage of the sealedpackage at accelerated conditions for at least 6 months.

In one embodiment of the sealed package, the pharmaceutical compositionfurther comprises no more than 2 wt% of a pH adjuster. In one embodimentof the sealed package, the pharmaceutical composition is in the form ofan immediate release tablet. In one embodiment of the sealed package,the pharmaceutical composition comprises, by weight, between 1% and 4%esketamine hydrochloride, no more than 2% of a pH adjuster and no morethan 5% of2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one.

In one embodiment of the sealed package, the pharmaceutical compositionis prepared by wet granulation. In one embodiment of the sealed package,the granulate is a milled granulate. In one embodiment of the sealedpackage, the granulate is both wet granulated and milled. In oneembodiment of the sealed package, the granulate is both wet and drymilled. In one embodiment of the sealed package, the sealed package isan HDPE bottle.

The present disclosure also provides a process for preparing thepharmaceutical composition described herein or the sealed packagedescribed herein, comprising: a. obtaining esketamine hydrochloride drugsubstance; b. determining the total amount of2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one presentin the esketamine hydrochloride drug substance; and c. including theesketamine hydrochloride drug substance in the preparation of thepharmaceutical composition, drug substance determined to have less than0.10 wt% by weight of2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one.

The present disclosure also provides a process for preparing apharmaceutical composition comprising esketamine hydrochloride and apharmaceutically acceptable carrier, wherein the pharmaceuticalcomposition comprises less than 5 wt% of2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one,comprising: a. obtaining esketamine hydrochloride drug substance; b.determining the total amount of2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one presentin the esketamine hydrochloride drug substance; and c. including theesketamine hydrochloride drug substance in the preparation of thepharmaceutical composition drug substance determined to have less than0.10 wt% of2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one.

The present disclosure also provides a process for validating a batch ofa pharmaceutical composition containing esketamine hydrochloride and atleast one pharmaceutically acceptable carrier for distributioncomprising:

-   a. determining the total amount of    2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one in    a sample of the batch after stability testing; and-   b. validating the batch for distribution the batch determined in    step a) to contain less than 5 wt% of    2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one.

In one embodiment of the process, the batch validated for distributionis determined in step a) to contain less than 1.0 wt% of2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one. Inanother embodiment of the process, the batch validated for distributionis determined in step a) to contain less than 0.5 wt% of2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one. Inanother embodiment of the process, the batch validated for distributionis determined in step a) to contain less than 0.2 wt% of2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one. Inanother embodiment of the process, the batch validated for distributionis determined in step a) to contain less than 0.1 wt% of2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one.

The present disclosure also provides a process for making the isolatedcompound2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-onecomprising: a. contacting esketamine hydrochloride with a pH-sensitivepolymer and b. isolating the compound from the reaction mixture of stepa). In one embodiment of the method, the compound is isolated from themixture via chromatography. In one embodiment of the method, thecompound is isolated from the mixture via lyophilization.

The present disclosure also provides for a method of determining thelevel of2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one inesketamine hydrochloride drug substance, comprising

-   a) Measuring by HPLC the area under a peak corresponding to    esketamine in a reference standard at a known level;-   b) Measuring by HPLC the area under a peak corresponding to    2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one in    a sample comprising esketamine hydrochloride and    2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one;-   c) Determining the amount of    2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one in    the sample by comparing the area of Step (a) to the area of Step (b)    and taking into account the relative response factor between    2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one and    esketamine.

The present disclosure also provides for the use of2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one as areference standard in the preparation of batches of pharmaceuticalcompositions comprising esketamine or a pharmaceutically acceptable saltthereof.

As used throughout the present disclosure, “drug substance” or “DS”refers to the active ingredient in a drug product, which providespharmacological activity or other direct effect in the diagnosis, cure,mitigation, treatment, or prevention of disease, or to affect thestructure or any function of the body of man or animals. As usedthroughout the present disclosure, “drug product” or “DP” refers to thefinished dosage form containing the drug substance as well as at leastone pharmaceutically acceptable carrier.

As used throughout the present disclosure, a “sealed” package, containeror coating substantially prevents the atmosphere from coming in contactwith the contents of the package or container or with the materialcoated by the coating. As used throughout the present disclosure, an“HDPE” bottle refers to a bottle constructed of high densitypolyethylene plastic.

Referring to FIGS. 1A and 1B, a dosage form can include particles 10Athat contain esketamine. The particle (e.g., coated particle or“core-shell” particle) can include a core 12A (or “uncoated core”),which may be coated with one or more layers, films or coatings, e.g.,14a, 16a, or any additional layer or coating that is coated over,underneath, or intermediate to these. In FIGS. 1B and 1C, the layerdesignated 16A may be a drug-containing layer, and the layer designatedas 14A may be a solvent resistant, e.g., a pH sensitive film layer.Particle 10A can contain one or more of the ingredients describedherein, such as esketamine, a gelling polymer, optional wax, optionalsolvent-resistant layer, as well as one or more additional layer orlayers under, over, or intermediate to these layers or between eitherlayer and the core. Each layer can be present in size or amount (e.g.,thickness) that will result in a useful immediate release dosage formhaving one or more of the presently described abuse deterrent features.Other optional components of a core or layer of particle 10A can befiller, binder, other excipient, or solvent (not more than a residualamount, if any) such as water or ethanol for use in preparing the coatedparticle, and that is substantially removed after formation of the core,coating, or coated particle. Examples of the core 10A can include anyamount or combination of the different ingredients of: a gelling polymer(e.g., from 0 to 100 percent of a core), filler as described herein suchas sugar (mannitol) or microcrystalline cellulose (e.g., from 0 to 100percent of a core), binder (e.g., from 0 to 100 percent of a core), andwax (e.g., from 0 to 100 percent of a core).

While the present dosage forms containing core-shell particles 10A arenew and inventive, certain method steps useful to prepare theseparticles may be known. Available methods include certain methods andprocessing steps known to be useful for preparing particles and coatedparticles in the pharmaceutical arts. A core-shell particle 10A can beprepared by an initial step of mixing ingredients of core 12A with asolvent such as water or ethanol and forming the mixture into aspherical core particle by known methods. The particle may be dried andseparated by size, and then one or more coating in the form of acontinuous film or layer can be applied to the core, optionallysuccessively to produce multiple layers surrounding the core. Generalprocessing to produce a multi-layer coated particle can include a seriesof steps such as compounding, mixing, granulation, wet milling, drymilling, coating (by any method such as fluidized bed coating, spraycoating, etc.), and one or more drying steps such as by use of afluidized bed or other drying method. Intermittently betweencore-forming and coating steps, e.g., after a drying step, coated oruncoated particles can be sorted or separated based on size to produce acomposition or a collection of particles having a desired size range anddistribution. Accordingly, coated granulate compositions according tothe invention may be prepared by a process comprising:

-   (i) granulating a wax or a gelling polymer, or a mixture thereof, in    the presence of a hydroalcoholic solution or suspension comprising a    suitable binder, to form granules;-   (ii) layering the granules formed in step (i) with a solution or    suspension comprising esketamine; and-   (iii) coating the layered granules formed in step (ii) with a    solution or suspension comprising a film forming polymer material to    form a coated layered granulate. The process above may further    comprise steps of milling and drying the granulate formed in step    (i). The hydroalcoholic solution can contain any ratio of water to    ethanol (e.g. 10:30, 10:35, 10:40, 10:45, 10:50, 10:55, 10:60,    10:65, 10:70, 10:75, 10:80, 10:85, 10:90, 15:30, 15:35, 15:40,    15:50, 15:55, 15:65, 15:70, 15:80, 15:85, 20:30, 20:35, 20:45,    20:50, 20:55, 20:65, 20:70, 20:75, 20:85, 20:90, 25:30, 25:35,    25:40, 25:45, 25:55, 25:60, 25:65, 25:70, 25:80, 25:85, 25:90,    30:35, 30:40, 30:50, 30:55, 30:65, 30:70, 30:75, 30:80, 30:85) and    can contain any ratio of the gelling polymer (e.g. 1 part in mix to    3 parts in solution, 1 part in mix to 2 parts in solution, 1 part in    mix to 1 part in solution, 2 part in mix to 1 parts in solution, 2    part in mix to 3 parts in solution, 3 part in mix to 1 parts in    solution, or 3 part in mix to 2 parts in solution).

In instances wherein the core comprises a sugar sphere or amicrocrystalline cellulose sphere, the steps of the process above wouldbe modified as follows:

-   (i) providing a sugar sphere (or microcrystalline cellulose sphere);-   (ii) layering the sugar sphere (or microcrystalline cellulose    sphere) with a solution or suspension comprising an API; and-   (iii) coating the layered sphere formed in step (ii) with a solution    or suspension comprising a film forming polymer material to form a    coated layered sphere.

Compressed tablets according to the invention may be prepared by aprocess comprising:

-   (i) combining the coated layered granulate (or the coated layered    sphere) prepared according to either of the above processes with a    second API (e.g., acetaminophen), a gelling polymer, and a    disintegrant, and optionally, with at least one additional excipient    selected from a filler, a colorant, and a pH adjusting agent, to    form a first mixture and then blending the first mixture for a    suitable time;-   (ii) adding a lubricant to the blended mixture formed in step (i) to    form a second mixture, and then blending the second mixture for a    suitable time;-   (iii) compressing the blended mixture formed in step (ii) to form    compressed tablets.

A suitable time for the blending in step (i) may be, for example, fromabout 5 to about 90 minutes, or from about 10 to about 60 minutes, orfrom about 20 to about 40 minutes, or about 30 minutes. A suitable timefor the blending in step (ii) may be, for example, from about 1 to about30 minutes, or from about 5 to about 20 minutes, or about 10 minutes.

In certain embodiments as shown at FIGS. 1A, 1B, and 1C, an immediaterelease dosage form as described can include a core-shell particle 10Athat includes a core 12A that contains no drug, only a minor amount ofAPI, or an insubstantial amount of API. Core 12A may contain less than 5weight percent, e.g., less than 1 or less than 0.5 weight percent activepharmaceutical ingredient based on a total weight of the core of thecore-shell particle. Alternatively, core 12A may contain less than 5weight percent of a total amount of pharmaceutical ingredient in acore-shell polymer, e.g., less than 5, less than 1, or less than 0.5weight percent active pharmaceutical ingredient based on total weight ofAPI in the core-shell particle. In these embodiments a major portion ofAPI can be contained outside of core 12A, e.g., in an API layer 16A,which can contain at least 50, at least 75, or at least 90, or at least95 weight percent of a total amount of the API in a core-shell polymer.

Core 12A can include binder, gelling polymer (e.g., HPMC), wax, filler,or any combination thereof, each in an amount to allow the materials ofthe core to function as one or more abuse deterrent features asdescribed herein. See the examples included herewith for examples ofuseful amounts and ranges of amounts of these ingredients. In apreferred embodiment, core 12A includes HPMC, glyceryl behenate, andethylcellulose.

Referring to FIG. 1A, core 12A contains gelling polymer, wax, binder, orfiller, or any combination of these, and no API (meaning not more thanan insignificant amount, such as less than 0.5, less than 0.1, or zeroweight percent based on the weight of core 12A). As shown at FIGS. 1Band 1C, core 12A, not containing API, can be coated with a coating layerthat contains API, e.g., an active pharmaceutical layer or API layer16A. As shown at FIG. 1B, core-shell particle 10A includes core 12A,which does not contain any API, and API layer 16A, which contains anamount of API, such as a total amount of API (e.g., API commonlysusceptible to abuse) to be contained in a dosage form prepared fromparticles 10A. API layer 16A can contain one or more ingredients asdescribed herein useful to form API layer 16A as a layer over an outersurface of core 12A. API in API layer 16A can account for all of or mostof (e.g., at least 70, at least 80, at least 90, or at least 95 percent)the total amount of that type of API in the core-shell particles and inthe dosage form; in this embodiment, the core can contain less than 10,less than 5, or less than 1 percent of the total amount of API in thecore-shell particles, and less than 10, 5, or 1 percent of the totalamount of API in the dosage form. Useful non-API ingredients in an APIlayer can include a binder or a gelling polymer along with the API. TheAPI and non-API ingredients can be carried in a solvent (e.g., water,ethanol, or both) and coated and dried to form a preferably continuousfilm layer on an outer surface of core 12A, i.e., API layer 16A. See theexamples included herewith for examples of useful amounts and ranges ofamounts of these ingredients. In a preferred embodiment, the API layer16A includes esketamine and hypromellose (HPMC).

A core-shell particle 10A can also optionally include a film layer,e.g., a solvent-resistant layer (e.g., a pH-sensitive layer) 14A asdescribed herein.

In certain alternate embodiments a dosage form as described can includea core-shell particle 10B that includes a core 12B that does contain auseful amount of API, such as an amount of API useful in an immediaterelease dosage form having one or more abuse deterrent features asdescribed herein, prepared to include particles 10B. See FIGS. 2A and2B. According to such embodiments, core 12B of particle 10B can containa gelling polymer, optional wax, optional binder or filler, and anamount of API.

Referring to FIG. 2A, core 12B contains gelling polymer, optional wax,optional binder, and API. Referring to FIG. 2B, core 12B, containingAPI, can optionally be coated with solvent-resistant layer (e.g., apH-sensitive layer) 14B as described herein for use in an immediaterelease dosage form. Core 12B may also optionally be coated with acoating layer that contains API, e.g., an active pharmaceutical layer orAPI layer prior to application of the solvent-resistant layer.Accordingly, API containing core-shell particles as described herein maycontain API of a type that is susceptible to abuse:

-   in an API layer surrounding the core and in a substantial amount in    the core;-   in an API layer surrounding the core and in an insubstantial amount    in the core;-   only in an API layer surrounding the core; or-   only in the core.

In certain alternative embodiments, a dosage form as described caninclude a core-shell particle 10B, as depicted in FIG. 2B, that thatdoes not contain an API layer, and does not contain any API. Referringto FIG. 2C, such a particle 10B, containing no API, may include core 12Bcontaining gelling polymer, optional wax, and optional binder, whichcore 12B may optionally be coated with solvent-resistant layer (e.g., apH-sensitive layer) 14B as described herein for use in an immediaterelease dosage form. In a preferred embodiment of a core-shell particle10B that does not contain an API layer, the core includes Hypromellose,glyceryl behenate, and ethylcellulose.

A coated particle 10A or 10B that includes API, and optionally, a coatedparticle 10B that does not include API, can be included in any of avariety of dosage forms, examples including a compressed tablet orcompressed capsule, a suppository, capsule, caplet, pill, gel, softgelatin capsule, etc. As one example, a dosage form 12 can be preparedas a compressed tablet or compressed capsule. Tablet or capsule 12 cancontain core-shell particles 10 (e.g., 10A or 10B) distributed within amatrix 20, compressed to form the compressed tablet or capsule 12.Core-shell particles 10A or 10B can be as described herein, generally orspecifically, and can contain an amount of API suited to provide adesired dosage upon ingestion of tablet or capsule 12; e.g., matrix 20does not include any substantial amount of API, or contains no API atall.

Matrix 20 can include ingredients useful in combination with thecore-shell particles 10A, 10B, to produce an immediate release dosageform. Examples of useful excipients of an immediate release dosage formcan include ingredients that allow the dosage form to break up ordisintegrate upon ingestion and facilitate exposure to fluid in astomach, such as a useful amount of disintegrant. Examples of suchexcipients for such a dosage form can also include one or moreingredients that act as an abuse deterrent feature, such as a gellingpolymer as described herein. Other excipients can be useful forprocessing to form a compressed dosage form, and also may allow thecompressed dosage form to function as an immediate release dosage form,with one or more abuse deterrent features. In certain embodiments, thematrix includes a filler, a disintegrant, a binder, a gelling polymer, apH adjuster, a glidant, and a lubricant.

The present disclosure also pertains to and includes at least thefollowing aspects:

Aspect 1. An abuse resistant oral dosage form for the administration ofesketamine to a subject comprising:

-   (i) a first population of core-shell particles, each of the    core-shell particles of the first population comprising    -   a core,    -   an active pharmaceutical layer surrounding the core, the active        pharmaceutical layer comprising esketamine or a pharmaceutically        acceptable salt thereof, and    -   at least one layer surrounding the active pharmaceutical layer,        the at least one layer comprising a pH-sensitive film comprising        a pH-sensitive polymer that is insoluble in water at a pH        greater than 5; and,-   (ii) a matrix comprising a carbomer gelling polymer and sodium    bicarbonate, wherein the carbomer gelling polymer and sodium    bicarbonate are present in a ratio by weight percentage of about 2:2    based on the total weight of the dosage form;

-   wherein the dosage form exhibits an immediate release profile of    esketamine having not less than 90% of the esketamine released in 60    minutes, wherein the release profile is evaluated by dissolution of    the tablet in 300 mL of 0.1N HC1 media using USP II apparatus at 50    RPM paddle speed and 37° C.; and,-   wherein the dosage form exhibits an immediate release profile of the    esketamine when administered to a human in therapeutic doses, and an    extended release profile of the esketamine when administered to a    human in supratherapeutic doses, or-   wherein the dosage form exhibits abuse resistant properties when    physically manipulated, or-   wherein the dosage form exhibits abuse resistant properties when    physically manipulated and administered in a manner not consistent    with oral dosing, or-   wherein the dosage form exhibits abuse resistant properties when    administered in a manner intended to result in administration of the    esketamine in a higher than therapeutic dose.

Aspect 2. The dosage form according to aspect 1, wherein when the dosageform is physically manipulated by crushing to form a population ofparticles, less than 15% of the population comprises a subpopulation ofparticles having a particle size of less than 75 µm.

Aspect 3. The dosage form according to any preceding aspect, whereinwhen the dosage form is physically manipulated by crushing to form apopulation of particles, less than 40 wt.% of the population ofparticles comprises a subpopulation of particles having a particle sizeof less than 106 µm, and wherein said subpopulation contains less than10 wt.% base equivalent of the esketamine of said dosage form.

Aspect 4. The dosage form according to any preceding aspect, whereinwhen the dosage form is physically manipulated by crushing to form apopulation of particles, less than 35 wt.% comprises a subpopulation ofparticles having a particle size of 212-500 µm and containing less than70 wt.% base equivalent of the esketamine of said dosage form.

Aspect 5. The dosage form according to any preceding aspect, whereinwhen the dosage form is physically manipulated by crushing to form apopulation of particles, less than 30 wt.% comprises a subpopulation ofparticles having a particle size of 106-212 µm and wherein thesubpopulation of particles contains less than 20 wt.% base equivalent ofthe esketamine of said dosage form.

Aspect 6. The dosage form according to aspect 1, wherein the dosage formexhibits one or more of the abuse resistant properties when the dosageform is physically manipulated by crushing and subsequent heating priorto the administration in a manner not consistent with oral dosing or ina manner intended to result in administration of the esketamine in ahigher than therapeutic dose.

Aspect 7. The dosage form according to aspect 6, wherein the heatingcomprises subjecting the physically manipulated dosage form to atemperature of about 200° C.-300° C.

Aspect 8. The dosage form according to aspect 6 or aspect 7, wherein thephysically manipulated dosage form is heated for at least one minute.

Aspect 9. The dosage form according to aspect 7 or aspect 8, wherein theheated, physically manipulated dosage form releases less esketamine(base equivalent) after incubation in water or 0.1 N HCl for up to 18hours, as compared to the release of esketamine from a physicallymanipulated dosage form control that has not been heated prior toincubation in water or 0.1 N HCl for up to 18 hours.

Aspect 10. The dosage for according to aspect 7 or aspect 8, wherein theheated, physically manipulated dosage form releases at least 20 wt.%less esketamine (base equivalent), as compared to the release ofesketamine (base equivalent) from a physically manipulated dosage formcontrol that has not been heated prior to incubation in water or 0.1 NHCl for up to 18 hours.

Aspect 11. The dosage form according to any one of the precedingaspects, wherein upon physically manipulating the dosage form bycrushing, the physically manipulated dosage form exhibits less than 5wt.% the esketamine diffusion of powdered pure esketamine or apharmaceutically acceptable salt thereof, over 60 minutes across amembrane having a molecular weight cutoff of 12-14 kD from a receptorchamber containing a phosphate buffer at pH 6.4 and maintained at 37° C.

Aspect 12. The dosage form according to any one of the precedingaspects, wherein upon physically manipulating the dosage form bycrushing, the physically manipulated dosage form exhibits lessesketamine diffusion across nasal membranes of a human subject whennasally insufflated by the subject, relative to a solution of 140 mg/mlesketamine (base equivalent) in pH 4.5 citrate buffer.

Aspect 13. The dosage form according to aspect 12, wherein uponphysically manipulating the dosage form by crushing, the physicallymanipulated dosage form exhibits less than 5% the relative esketaminediffusion of a solution of 140 mg/ml esketamine (base equivalent) in pH4.5 citrate buffer, over 60 minutes across a membrane having a molecularweight cutoff of 12-14 kD from a receptor chamber containing a phosphatebuffer at pH 6.4 and maintained at 37° C.

Aspect 14. The dosage form according to any one of the precedingaspects, wherein upon physically manipulating the dosage form bycrushing, the absorption of esketamine from the physically manipulateddosage form over 60 minutes across a membrane having a molecular weightcutoff of 12-14 kD from a receptor chamber containing a phosphate bufferat pH 6.4 and maintained at 37° C. is less than 20%.

Aspect 15. The dosage form according to any one of the precedingaspects, wherein the dosage is in a compressed tablet form.

Aspect 16. The dosage form according to any one of the precedingaspects, wherein the dosage form further comprises a second populationof core-shell particles that do not contain an active pharmaceuticallayer.

Aspect 17. The dosage form according to aspect 16, wherein each of thecore-shell particles of the second population comprise a core thatincludes a gelling polymer and a wax, and at least one layer surroundingthe core, the at least one layer comprising a pH-sensitive filmcomprising a pH-sensitive polymer that is insoluble in water at a pHgreater than 5.

Aspect 18. The dosage form according to any one of the precedingaspects, wherein the core of each of the core-shell particles of thefirst population does not include a sugar sphere or an activepharmaceutical ingredient.

Aspect 19. The dosage form according to any one of the precedingaspects, wherein the gelling polymer in the core of the core-shellparticles of the first population is selected from the group consistingof ethylcellulose, cellulose acetate, cellulose acetate propionate,cellulose acetate butyrate, cellulose acetate phthalate, cellulosetriacetate, cellulose ether, cellulose ester, cellulose ester ether,cellulose, hydroxypropyl methyl cellulose, hydroxy methyl cellulose,methyl cellulose, hydroxyethylmethyl cellulose, sodium carboxymethylcellulose, a carbomer polymer, polyethylene oxide, and combinationsthereof.

Aspect 20. The dosage form according to aspect 19, wherein the gellingpolymer in the core of the core-shell particles of the first populationis hydroxypropyl methyl cellulose.

Aspect 21. The dosage form according to any one of the precedingaspects, wherein the wax in the core of the core-shell particles of thefirst population is a fatty alcohol that is selected from glycerolbehenate, glycerol palmitostearate, glycerol monostearate, and stearoylmacroglycerides.

Aspect 22. The dosage form according any one of the preceding aspects,wherein the pH-sensitive polymer in the core-shell particles of thefirst population is a copolymer of dimethyl aminoethyl methacrylate,butyl methacrylate, and methyl methacrylate monomers.

Aspect 23. The dosage form according to any one of the precedingaspects, wherein the supratherapeutic dose is five or more dosage formunits.

Aspect 24. The dosage form according to any one of the precedingaspects, wherein the supratherapeutic dose is 10 dosage form units.

Aspect 25. The dosage form according any one of the preceding aspects,wherein supratherapeutic doses of said dosage form produce a gel in 15minutes or less, following exposure to an aqueous medium comprising0.025 N HCl and 70 mM NaCl at 37° C.

Aspect 26. The dosage form according to aspect 25, wherein when a dualscreen apparatus comprising a top screen and a bottom screen is used toextract at least a portion of said gel from said medium, a firstquantity of the gel adheres to a lower surface of the top screen of theapparatus and a second quantity of the gel adheres to a upper surface ofthe bottom screen of the apparatus, wherein the vertical thickness ofthe second quantity is at least twice the vertical thickness of thefirst quantity.

Aspect 27. The dosage form according to aspect 25, wherein said gel issubstantially uniformly dispersed within said medium.

Aspect 28. The dosage form according to any one of the preceding aspectscomprising esketamine HCl.

Aspect 29. An oral tablet for the administration of esketamine to asubject comprising:

-   a total weight of not less than 800 mg, and having 40 mg of    esketamine (base equivalent), the esketamine (base equivalent)    representing less than 5.0% by weight of the total weight of the    tablet, or-   a total weight of not less than 571 mg, and having 20 mg of    esketamine (base equivalent), the esketamine (base equivalent)    representing less than 3.5% by weight of the total weight of the    tablet;

-   wherein the tablet exhibits an immediate release profile of    esketamine having not less than 90% of the esketamine released in 60    minutes, and wherein the release profile is evaluated by dissolution    of the tablet in 300 mL of 0.1N HC1 media using USP II apparatus at    50 RPM paddle speed and 37° C.; and-   wherein the tablet exhibits an immediate release profile of the    esketamine when administered to a human in therapeutic doses, and an    extended release profile of the esketamine when administered to a    human in supratherapeutic doses, or-   wherein the tablet exhibits abuse resistant properties when    physically manipulated, or-   wherein the tablet exhibits abuse resistant properties when    physically manipulated and administered in a manner not consistent    with oral dosing, or-   wherein the tablet exhibits abuse resistant properties when    administered in a manner intended to result in administration of the    esketamine in a higher than therapeutic dose.

Aspect 30. The tablet according to aspect 29, wherein when the tablet isphysically manipulated by crushing to form a population of particles,less than 15% of the population comprises a subpopulation of particleshaving a particle size of less than 75 µm.

Aspect 31. The tablet according to aspect 29 or 30, wherein when thetablet is physically manipulated by crushing to form a population ofparticles, less than 40 wt.% of the population of particles comprises asubpopulation of particles having a particle size of less than 106 µm,and wherein said subpopulation contains less than 10 wt.% baseequivalent of the esketamine of said tablet.

Aspect 32. The tablet according to any one of aspects 29 to 31, whereinwhen the tablet is physically manipulated by crushing to form apopulation of particles, less than 35 wt.% comprises a subpopulation ofparticles having a particle size of 212-500 µm and containing less than70 wt.% base equivalent of the esketamine of said tablet.

Aspect 33. The tablet according to anyone of aspects 29 to 32, whereinwhen the tablet is physically manipulated by crushing to form apopulation of particles, less than 30 wt.% comprises a subpopulation ofparticles having a particle size of 106-212 µm and wherein thesubpopulation of particles contains less than 20 wt.% base equivalent ofthe esketamine of said tablet.

Aspect 34. The tablet according to aspect 29, wherein the tabletexhibits one or more of the abuse resistant properties when the tabletis physically manipulated by crushing and subsequent heating prior tothe administration in a manner not consistent with oral dosing or in amanner intended to result in administration of the esketamine in ahigher than therapeutic dose.

Aspect 35. The tablet according to aspect 34, wherein the heatingcomprises subjecting the physically manipulated tablet to a temperatureof about 200° C.-300° C.

Aspect 36. The tablet according to aspect 34 or aspect 35, wherein thephysically manipulated tablet is heated for at least one minute.

Aspect 37. The tablet according to aspect 34 or aspect 35, wherein theheated, physically manipulated tablet releases less esketamine (baseequivalent) after incubation in water or 0.1 N HCl for up to 18 hours,as compared to the release of esketamine from a physically manipulatedtablet control that has not been heated prior to incubation in water or0.1 N HCl for up to 18 hours.

Aspect 38. The tablet according to aspect 34 or aspect 35, wherein theheated, physically manipulated tablet releases at least 20 wt.% lessesketamine (base equivalent), as compared to the release of esketamine(base equivalent) from a physically manipulated tablet control that hasnot been heated prior to incubation in water or 0.1 N HCl for up to 18hours.

Aspect 39. The tablet according to any one of aspects 29 to 38, whereinupon physically manipulating the tablet by crushing, the physicallymanipulated tablet exhibits less than 5 wt.% the esketamine diffusion ofpowdered pure esketamine or a pharmaceutically acceptable salt thereof,over 60 minutes across a membrane having a molecular weight cutoff of12-14 kD from a receptor chamber containing a phosphate buffer at pH 6.4and maintained at 37° C.

Aspect 40. The tablet according to any one of aspects 29 to 39, whereinupon physically manipulating the tablet by crushing, the physicallymanipulated tablet exhibits less esketamine diffusion across nasalmembranes of a human subject when nasally insufflated by the subject,relative to a solution of 140 mg/ml esketamine (base equivalent) in pH4.5 citrate buffer.

Aspect 41. The tablet according to aspect 40, wherein upon physicallymanipulating the tablet by crushing, the physically manipulated tabletexhibits less than 5% the relative esketamine diffusion of a solution of140 mg/ml esketamine (base equivalent) in pH 4.5 citrate buffer, over 60minutes across a membrane having a molecular weight cutoff of 12-14 kDfrom a receptor chamber containing a phosphate buffer at pH 6.4 andmaintained at 37° C.

Aspect 42. The tablet according to any one of aspects 29 to 41, whereinupon physically manipulating the tablet by crushing, the absorption ofesketamine from the physically manipulated tablet over 60 minutes acrossa membrane having a molecular weight cutoff of 12-14 kD from a receptorchamber containing a phosphate buffer at pH 6.4 and maintained at 37° C.is less than 20%.

Aspect 43. The dosage form according to any one of aspects 29 to 42comprising esketamine HCl.

Aspect 44. An oral dosage form comprising:

-   (i) a first population of core-shell particles, each of the    core-shell particles of the first population comprising    -   a core that includes a gelling polymer and a wax;    -   an active pharmaceutical layer surrounding the core, the active        pharmaceutical layer comprising esketamine; and    -   at least one layer surrounding the active pharmaceutical layer,        the at least one layer comprising a pH-sensitive film comprising        a pH-sensitive polymer that is insoluble in water at a pH        greater than 5; and,-   (ii) a matrix comprising a carbomer gelling polymer and sodium    bicarbonate, wherein the carbomer gelling polymer and sodium    bicarbonate are present in a ratio by weight percentage of about 2:2    based on the total weight of the dosage form;

-   wherein the dosage form exhibits an immediate release profile of the    esketamine when administered to a human in therapeutic doses, and an    extended release profile of the esketamine when administered to a    human in supratherapeutic doses.

Aspect 45. The dosage form according to aspect 44, wherein the dosage isin a compressed tablet form.

Aspect 46. The dosage form according to aspect 44 or aspect 45, whereinthe dosage form further comprises a second population of core-shellparticles that do not contain an active pharmaceutical layer.

Aspect 47. The dosage form according to aspect 46, wherein each of thecore-shell particles of the second population comprise a core thatincludes a gelling polymer and a wax, and at least one layer surroundingthe core, the at least one layer comprising a pH-sensitive filmcomprising a pH-sensitive polymer that is insoluble in water at a pHgreater than 5.

Aspect 48. The dosage form according to any one of aspects 44-47,wherein the core of each of the core-shell particles of the firstpopulation does not include a sugar sphere or an active pharmaceuticalingredient.

Aspect 49. The dosage form according to any one of aspects 44-48,wherein the gelling polymer in the core of the core-shell particles ofthe first population is selected from the group consisting ofethylcellulose, cellulose acetate, cellulose acetate propionate,cellulose acetate butyrate, cellulose acetate phthalate, cellulosetriacetate, cellulose ether, cellulose ester, cellulose ester ether,cellulose, hydroxypropyl methyl cellulose, hydroxy methyl cellulose,methyl cellulose, hydroxyethylmethyl cellulose, sodium carboxymethylcellulose, a carbomer polymer, polyethylene oxide, and combinationsthereof.

Aspect 50. The dosage form according to aspect 49, wherein the gellingpolymer in the core of the core-shell particles of the first populationis hydroxypropyl methyl cellulose.

Aspect 51. The dosage form according to any one of aspects 44-50,wherein the wax in the core of the core-shell particles of the firstpopulation is a fatty alcohol that is selected from glycerol behenate,glycerol palmitostearate, glycerol monostearate, and stearoylmacroglycerides.

Aspect 52. The dosage form according any one of aspects 44-51, whereinthe pH-sensitive polymer in the core-shell particles of the firstpopulation is a copolymer of dimethyl aminoethyl methacrylate, butylmethacrylate, and methyl methacrylate monomers.

Aspect 53. The dosage form according to any one of aspects 44-52,wherein the supratherapeutic dose is five or more dosage form units.

Aspect 54. The dosage form according to any one of aspects 44-53,wherein the supratherapeutic dose is 10 dosage form units.

Aspect 55. The dosage form according any one of aspects 44-54, whereinsupratherapeutic doses of said dosage form produce a gel in 15 minutesor less, following exposure to an aqueous medium comprising 0.025 N HCland 70 mM NaCl at 37° C.

Aspect 56. The dosage form according to aspect 55, wherein when a dualscreen apparatus comprising a top screen and a bottom screen is used toextract at least a portion of said gel from said medium, a firstquantity of the gel adheres to a lower surface of the top screen of theapparatus and a second quantity of the gel adheres to a upper surface ofthe bottom screen of the apparatus, wherein the vertical thickness ofthe second quantity is at least twice the vertical thickness of thefirst quantity.

Aspect 57. The dosage form according to aspect 56, wherein said gel issubstantially uniformly dispersed within said medium.

Aspect 58. The dosage form according to any one of aspects 44-57comprising esketamine HCl.

Aspect 59. A method of reducing the potential for abuse by a human of anactive pharmaceutical ingredient comprising esketamine, comprisingproviding to the human a dosage form according to any one of aspects1-58.

Aspect 60. A method of reducing the potential for abuse by a human of anactive pharmaceutical ingredient comprising esketamine by simultaneousoral ingestion of multiple dosage units comprising the activepharmaceutical ingredient, comprising providing to the human a dosageform according to any one of aspects 1-58.

Aspect 61. A method for treating or preventing pain or discomfort in asubject in need thereof by administering to the subject a dosage formaccording to any one of aspects 1-58.

Aspect 62. A method for treating depression in a subject in need thereofby administering to the subject a dosage form according to any one ofaspects 1-58.

Aspect 63. A method of reducing the potential for abuse by nasalinsufflation by a human of an active pharmaceutical ingredientcomprising esketamine, comprising providing to the human a dosage formaccording to any one of aspects 1-58.

The following non-limiting examples show various dosage forms asdescribed herein. The described and exemplified dosage forms can be madefrom methods that include granulating, coating, and compressing steps asfollows.

Example 1 - General Procedure for Preparation of Tablet Dosage FormGranulation

1. Glyceryl behenate and hypromellose K100M were dry mixed in a highshear granulator. Hydroalcoholic solution of ethylcellulose was added.Alternatively, the granulation can be produced through top spraying thehydroalcoholic solution in a fluid bed granulator. Optionally, a portionof the ethyl cellulose, for example from about 10 to about 50% byweight, or from about 10 to about 40% by weight, or from about 30 toabout 40% by weight, or from about 15 to about 30% by weight, may be drymixed with the glyceryl behenate and hypromellose K100M prior to addingthe hydroalcoholic solution containing the balance of the ethylcellulose.

Alternative approach when API is included in the core: Glyceryl behenateand hypromellose K100M and API are dry mixed in a high shear granulator.Hydroalcoholic solution of ethylcellulose is added. Alternatively, thegranulation can be produced through top spraying the hydroalcoholicsolution in a fluid bed granulator. Optionally, a portion of the ethylcellulose, for example from about 10 to about 50% by weight, or fromabout 10 to about 40% by weight, or from about 15 to about 30% byweight, is dry mixed with the glyceryl behenate and hypromellose K100Mprior to adding the hydroalcoholic solution containing the balance ofthe ethyl cellulose.

2. The granules were then wet milled using a size reduction mill(Granumill) and then dried using a fluid bed, and optionally screened.Optionally, the granules were subsequently then dry milled using a sizereduction mill.

Layering

3. The polymer granules were then layered using Wurster fluid bedlayering process with esketamine and hypromellose K100M (oralternatively, granulated using high shear granulation or top sprayfluid bed granulation process).

Alternative approach when API is not in the coated granule: the layeringstep is omitted and the coating of Step 4 below is applied to thegranulate prepared in Step 1.

Coating

4. The layered granules of Step 3 (or alternatively, when the coatedgranule will not contain API, the granules prepared in Step 1) were thencoated using a fluid bed coater equipped with a Wurster insert (bottomspray assembly) with ethanolic suspension of Eudragit E100 copolymer andmagnesium stearate. Coated particles were then screened and blended.

Blending and Tablet Compression

The blending, compression and bottling process for esketamine tabletsmanufactured using the coated intermediate is as follows:

-   1. The API-containing coated granules, crospovidone, Carbopol® 71G,    sodium bicarbonate, mannitol, microcrystalline cellulose,    optionally, coated granules containing no API, optionally, a glidant    such as colloidal silicon dioxide, and optionally a desired    colorant, were then added to the blender and mixed.-   2. Magnesium stearate (and optionally colorant) was then added to    the blender and mixed. The blend was compressed into tablets using a    rotary tablet press.

Example 2 - Preparation of Polymer Granules

Granules were manufactured in a high shear granulator, wherehypromellose and glyceryl behenate were dry mixed for 3 minutes. Then,either a 10% hydroalcoholic solution of ethylcellulose N10 was slowlyadded while maintaining the granulator impeller and chopper speed atpre-selected values that provide enough shear for granule formation andgrowth or 1 part ethylcellulose N10 was included in the dry mix and 2parts of a 10% 25:65 hydroalcoholic solution of ethylcellulose N10 wereslowly added while maintaining the granulator impeller and chopper speedat pre-selected values. Solution addition was continued until all theethylcellulose was added. The granules were then wet milled using a sizereduction mill (Granumill or Vector mixer) and were subsequently loadedinto fluid bed for drying followed, in certain cases, by the granulesbeing dry milled using a size reduction mill (Fitzmill). Table 1, below,provides the relative proportions of the reagents used for forming thegranules.

TABLE 1 Components for granule formulation Component % w/w HypromelloseK100M 60.09 Glyceryl behenate 25.75 Ethylcellulose N-10 14.16 TOTAL 100

The prepared granules were then layered in a bottom spray fluid bedcoater with an aqueous coating dispersion esketamine HCl andhypromellose 2910.

TABLE 2 Components for coating dispersion used for coating of polymergranules Component within Coating Dispersion % w/w g/Batch, 19.5%Esketamine g/Batch, 39.1% Esketamine Esketamine HCl 13 195 390Hypromellose 2910 5 75 150 Purified Water 82 1260 2520 TOTAL 100 15003000

TABLE 3 Components for layered granule formulation, 19.5% or 39.1%Esketamine HCl Layered Granule % w/w g/Batch, 19.5% Esketamine g/Batch,39.1% Esketamine Polymer granules from Table 1 68.83 596.1 325.4 Solidsfrom Coating Dispersion from Table 2 31.17 270 540 TOTAL 100 866.1 865.4

The esketamine HCl layered granules were then coated in a bottom sprayfluid bed coater with the alcoholic suspension of Eudragit E-100copolymer and magnesium stearate. The resulting coated granules(containing either 16% or 32% esketamine HCl) were subsequently used forfurther blending and compression process.

TABLE 4 Components for coating dispersion used for coating of EsketamineHCl layered granules Component within Coating Dispersion % w/w g/Batch,19.5% Esketamine g/Batch, 39.1% Esketamine Eudragit E100 16.67 102 102Magnesium Stearate 8.33 51 51 Alcohol USP 75 489 489 TOTAL 100 612 612

TABLE 5 Components for coated esketamine granules containing 16%Esketamine HCl Component % w/w Esketamine HCl layered granules, 19.5% 82Solids from coating dispersion from Table 4 18 TOTAL 100

TABLE 6 Components for coated esketamine granules containing 32%Esketamine HCl Component % w/w Esketamine HCl layered granules, 39.1% 82Solids from coating dispersion from Table 4 18 TOTAL 100

Coated polymer granules that did not contain esketamine HCl were formedusing the polymer granules of Table 1.

In order to form the coated polymer granules, polymer granules of Table1 were coated in a bottom spray fluid bed coater with the alcoholicsuspension of Eudragit E-100 copolymer and magnesium stearate (Table 7).The resulting coated granules were, along with the coated esketaminegranules, subsequently used for further blending and compressionprocess.

TABLE 7 Components for coating dispersion used for coating of polymergranules Component within Coating Dispersion % w/w g/Batch Eudragit E10016.67 366 Magnesium Stearate 8.33 182.8 Alcohol USP 75 1676 TOTAL 1002194.8

TABLE 8 Components for coated polymer granules (no esketamine) Component% w/w Polymer granules from Table 1 50 Solids from coating dispersionfrom Table 7 50 TOTAL 100

Example 3 - Esketamine HCl Tablet Formulation

The coated granules prepared according to Example 2, supra, were mixedwith excipients as listed in Tables 9-13, below, and blended in aV-blender for 30 minutes. Both coated esketamine granules (Tables ⅘ or4/6) and coated polymer granules (Tables ⅞) were included as indicated.Magnesium stearate was then added to lubricate the blend and the mixturewas blended for an additional 5 minutes prior to compressing intoesketamine HCl tablets.

TABLE 9 Tablets, 100 mg Esketamine % w/w Coated Esketamine Granules, 33%30.77 Coated Polymer Granules from Tables ⅞ 17.6 Mannitol (Mannogem EZ)13.39 Crospovidone (Polyplasdone XL) 20 Microcrystalline Cellulose(Avicel PH113) 13 Carbomer (Carbopol® 71G) 2 Sodium Bicarbonate 2Colloidal silicon dioxide 0.2 Magnesium stearate 1 Total 100

TABLE 10 Tablets, 40 mg Esketamine % mg/Tab g/batch Coated EsketamineGranules,16.0% 25.00 250.0 2500 Coated Polymer Granules 7.06 70.6 706Mannitol (Mannogem EZ) 29.74 297.4 2974 Crospovidone (Polyplasdone XL)20 200 2000 Microcrystalline Cellulose (Avicel PH113) 13 130 1300Carbomer (Carbopol® 71G) 2 20 200 Sodium Bicarbonate 2 20 200 Colloidalsilicon Dioxide 0.2 2 20 Magnesium stearate 1 10 100 Total 100 100010000

TABLE 11 Tablets, 20 mg Esketamine % mg/Tab g/batch Coated EsketamineGranules, 16.0% 12.5 125 1250* Coated Polymer Granules 21.17 211.7 2117*Mannitol (Mannogem EZ) 28.13 281.3 2813 Crospovidone (Polyplasdone XL)20 200 2000 Microcrystalline Cellulose (Avicel PH113) 13 130 1300Carbomer (Carbopol® 71G) 2 20 200 Sodium Bicarbonate 2 20 200 Colloidalsilicon Dioxide 0.2 2 20 Magnesium stearate 1 10 100 Total 100 100010000 *Polymer granules required 1766 (707+1059)

TABLE 12 Tablets, 10 mg Esketamine % mg/Tab g/batch Coated EsketamineGranules, 16.0% 6.25 62.5 625* Coated Polymer Granules 27.42 274.2 2742*Mannitol (Mannogem EZ) 28.13 281.3 2813 Crospovidone (Polyplasdone XL)20 200 2000 Microcrystalline Cellulose (Avicel PH113) 13 130 1300Carbomer (Carbopol® 71G) 2 20 200 Sodium Bicarbonate 2 20 200 Colloidalsilicon Dioxide 0.2 2 20 Magnesium stearate 1 10 100 Total 100 100010000 *Polymer granules required 1725 (354+1371)

TABLE 13 Tablets, 5 mg Esketamine % mg/Tab g/batch Coated EsketamineGranules, 16.0% 3.125 31.25 312.5* Coated Polymer Granules 30.545 305.453054.5* Mannitol (Mannogem EZ) 28.13 281.3 2813 Crospovidone(Polyplasdone XL) 20 200 2000 Microcrystalline Cellulose (Avicel® PH113)13 130 1300 Carbomer (Carbopol® 71G) 2 20 200 Sodium Bicarbonate 2 20200 Colloidal silicon Dioxide 0.2 2 20 Magnesium stearate 1 10 100 Total100 1000 10000 *Polymer granules required 1704 (177+1527)

Example 4 - Preparation of Comparative Embodiment

Comparative 20 and 100 mg esketamine HCl embodiments having a matrixcontaining carbomer gelling polymer and sodium bicarbonate in a ratio of2:10 percentage by weight, based on the total weight of the dosage form.

Esketamine HCl layered granules, as described in Example 2, were coatedin a bottom spray fluid bed coater with the alcoholic suspension ofEudragit E-100 copolymer and magnesium stearate. The resulting coatedgranules (containing 33% esketamine HCl) were subsequently used forfurther blending and compression process.

The coated granules were mixed with excipients as listed in Tables 14and 15, below, and blended in a V-blender for 30 minutes. Magnesiumstearate was then added to lubricate the blend and the mixture wasblended for an additional 5 minutes prior to compressing into esketamineHCl tablets.

TABLE 14 20 mg esketamine tablet formulations with 2:10 carbomer tosodium bicarbonate ratio % w/w Coated Esketamine Granules, 16% 11.7Coated Polymer Granules from Tables ⅞ 22.1 Mannitol (Mannogem EZ) 20Crospovidone (Polyplasdone XL) 20 Microcrystalline Cellulose (AvicelPH113) 13 Carbomer (Carbopol® 71G) 2 Sodium Bicarbonate 10 Colloidalsilicon dioxide 0.2 Magnesium stearate 1 Total 100

TABLE 15 100 mg esketamine tablet formulations with 2:10 carbomer tosodium bicarbonate ratio % w/w Coated Esketamine Granules, 33% 30.77Coated Polymer Granules from Tables ⅞ 17.6 Mannitol (Mannogem EZ) 5.37Crospovidone (Polyplasdone XL) 20 Microcrystalline Cellulose (AvicelPH113) 13 Carbomer (Carbopol® 71G) 2 Sodium Bicarbonate 10 Colloidalsilicon dioxide 0.2 Magnesium stearate 1 Red Iron Oxide 0.06 Total 100

Example 5 - Evaluation of Esketamine Release

Tablet dosage forms according to the present disclosure (100 mgesketamine HC1 - see Table 9, supra) were tested for single-tabletdissolution by depositing a single tablet into a USP II apparatuscontaining 500 mL of deaerated 0.01N hydrochloric acid medium and apaddle speed set at 50 RPM.

Also tested were comparative 100 mg esketamine HCl embodiments having amatrix containing carbomer gelling polymer and sodium bicarbonate in aratio of 2:10 percentage by weight, based on the total weight of thedosage form, that were prepared as described in Example 4, supra.

FIG. 4 shows the results of single-tablet dissolution testing of theinventive 2:2 dosage form (triangles) and the comparative 2:10 dosageform (squares). Both embodiments displayed complete release within 15minutes following deposition into the testing apparatus.

The respective dosage forms were also tested for the ability to providemultiple table abuse resistance (“MTAR”) when 12 individual dosage unitsare deposited into a USP II apparatus containing 400 mL of deaerated0.1N hydrochloric acid medium and a paddle speed set at 50 RPM. Theseconditions are intended to simulate oral ingestion by a potential abuserof a beverage with a supratherapeutic dose of the dosage forms.

FIG. 5 shows the results of multiple-tablet dissolution testing of theinventive 2:2 dosage form (triangles) and the comparative 2:10 dosageform (squares). Also tested was a second comparative dosage formcontaining 10 mg hydrocodone bitartrate and 325 mg acetaminophen(diamonds) as disclosed in WO 2016/094358 (see Example 23 on pages81-82). The inventive 2:2 dosage form displayed release of less than 60%of the active agent 30 minutes following deposition into the testingapparatus, and no more than 80% of the active agent 240 minutesfollowing deposition into the testing apparatus.

Example 6 - QbD Analysis

An evaluation was conducted to identify the optimized formulation withmaximized immediate release (IR) and MTAR dissolution properties.Sixteen different formulations varying the weight ratios of fourvariables (carbopol, sodium bicarbonate, crospovidone, coated polymergranules) in 100 mg API formulations were prepared according to theranges disclosed in Table 16.

TABLE 16 Ranges of Ingredients Evaluated Ingredient % w/w Carbopol 1 - 5Sodium bicarbonate 1 - 4 Crospovidone 10 - 30 Coated polymer granules1.82 - 28.82

The formulations were each assayed in dissolution media to assess therelease at 30 minutes for a single tablet (maximal IR) and the releasefor a multiple tablet at 60 minutes (minimal MTAR). The results aredisclosed in Table 17a (immediate release) and 17b (MTAR).

TABLE 17a Fastest Release At 30 Minutes Fastest formulation (ranking) %Carbopol % Sodium Bicarbonate 1 1.2 2.0 2 1.8 1.0 3 1.1 3.0 4 2.0 2.0 51.3 4.0 ... 15 4.8 3.2

TABLE 17b minimum release at 60 minutes Slowest formulation (ranking) %Carbopol % Sodium Bicarbonate 1 1.1 3.0 2 1.3 4.0 3 3.9 3.6 4 2.2 2.1 52.0 2.0 ... 10 4.8 3.2

The optimized formulations with the overall desirability maximizedcombining the contribution from IR and MTAR were analyzed based on atruncated 13 term model for MTAR and a 15 term model for IR with equalweightage to the two responses. The predicted optimized formulation isdisclosed in Table 18.

TABLE 18 Predicted Optimized Formulations Approach for OptimizationMaximize IR (15-term model) and minimize MTAR (13-term model) with equalweightage Optimized formulation composition (% w/w) Carbopol 1.02 Sodiumbicarbonate 2.62

Example 7 - Evaluation of Gel Characteristics

An evaluation was conducted to assess the quality of the gels that wereformed when respective supratherapeutic doses of the inventive 2:2weight percent dosage form and the comparative 1:2 and 2:10 weightpercent dosage forms were exposed to dissolution medium.

In particular, a supratherapeutic dose consisting of 10 tablets of theinventive 2:2 weight percent dosage form of Example 3 (Table 9) wasplaced into an aqueous medium of 0.025 N HCl + 70 mM NaCl at 37° C. Themedium also contained a dual mesh screen featuring ahorizontally-oriented circular top screen, a horizontally-orientedcircular bottom screen, and a handle for lifting the dual mesh apparatusfrom the medium. Fifteen minutes after mixing the depositedsupratherapeutic dose into the test medium, the dual mesh apparatus wasremoved from the medium and the characteristics of the gel were visuallyassessed.

The same procedure was performed with respect to a supratherapeutic doseof 10 tablets of the comparative 1:2 and 2:10 dosage forms of Table 19and Example 4 (Table 15), and the characteristics of the resulting gelwere assessed and compared to the gel resulting from thesupratherapeutic dose of the 2:2 inventive dosage form.

TABLE 19 100 Mg Esketamine Tablet Formulations With 1:2 Carbomer ToSodium Bicarbonate Ratio % w/w Coated Esketamine Granules, 32% 29.94Coated Polymer Granules from Tables ⅞ 16.82 Mannitol (Mannogem EZ) 16.04Crospovidone (Polyplasdone XL) 20 Microcrystalline Cellulose (AvicelPH113) 13 Carbomer (Carbopol® 71G) 1 Sodium Bicarbonate 2 Colloidalsilicon dioxide 0.2 Magnesium stearate 1 Total 100

All samples formed gels in under 15 minutes. Visual inspection of thedual screen apparatus that was lifted from the medium into which thesupratherapeutic dose of the 2:2 inventive dosage form was testedrevealed that the gel from the supratherapeutic dose (i) was retained onthe upper surface of the top screen in a very thin layer; (ii) wasretained on the lower surface of the top screen in a thin layer; (iii)was retained on the upper surface of the bottom screen in a robust layerthat was at least twice as thick (vertically) as the layer that wasretained on the lower surface of the top screen; and, (iv) overall,represented a good quality gel that was not overly rigid, nor was itwatery (was retained on the bottom screen and did not flow through thescreen when the apparatus was lifted from the medium). FIG. 6 providesan image of the dual screen apparatus that was used to test thesupratherapeutic dose of the 2:2 inventive dosage form with gel retainedon the screens as described above.

Visual inspection of the dual screen apparatus that was lifted from themedium into which the supratherapeutic dose of the 1:2 comparativedosage form was tested revealed that the gel from the supratherapeuticdose (i) was retained on the upper surface of the top screen in a weaklayer that was thinner than a layer that was retained on the uppersurface of the bottom screen; (ii) was retained on the lower surface ofthe top screen in a thin layer; (iii) was not retained between the topand bottom screens; and, (iv) appeared to flow through the screens as aweak gel. FIG. 7 provides an image of the dual screen apparatus that wasused to test the supratherapeutic dose of the 1:2 comparative dosageform with gel retained on the screens as described above.

Visual inspection of the dual screen apparatus that was lifted from themedium into which the supratherapeutic dose of the 2:10 comparativedosage form was tested revealed that the gel from the supratherapeuticdose (i) was retained on the upper surface of the top screen in a robustlayer that was thicker than a layer that was retained on the uppersurface of the bottom screen; (ii) was retained on the lower surface ofthe top screen in a thin layer; (iii) was retained on the upper surfaceof the top screen in a layer that was not as thick as the layer that wasretained on the upper surface of the top screen; (iv) included “runners”(portions of gel) between the layer of gel on the lower surface of thetop screen and the layer of gel on the upper surface of the bottomscreen, and, (v) overall, represented a rigid, thick gel. FIG. 8provides an image of the dual screen apparatus that was used to test thesupratherapeutic dose of the 2:10 comparative dosage form with gelretained on the screens as described above.

A further evaluation was conducted as to the quality of the gels thatwere formed when respective supratherapeutic doses of the inventive 2:2dosage form and the comparative 2: 10 dosage form were exposed todissolution medium.

A supratherapeutic dose consisting of 10 tablets of the inventive 2:2dosage forms of Example 3 (Table 9) was placed into an aqueous medium of0.025 N HCl + 70 mM NaCl at 37° C. The same procedure was performed in asecond test vessel with respect to a supratherapeutic dose of 10 tabletsof the comparative 2: 10 dosage form of Example 4 (Table 18), and thecharacteristics of the material within the vessel were assessed andcompared to the material within the vessel containing thesupratherapeutic dose of the 2:2 inventive dosage form.

FIG. 9 provides an image of the gel resulting from the supratherapeuticdose of the inventive 2:2 dosage forms, suspended in the test medium. Asshown, the gel / test medium mixture appeared turbid and opaque,indicating that the gel material was substantially homogeneouslydispersed within the medium. There were no uneven concentrations of gelin any particular region of the medium (e.g., in the upper, middle, orlower portions of the medium within the test vessel), such as in theform of clumps, and likewise no regions without association betweenmedium and gel, wherein medium is clearly visible in the absence of gelmaterial. These results suggest that supratherapeutic doses of theinventive dosage form would provide good resistance to an attempt toextract drug from the supratherapeutic dose by combining it with asolvent and then either orally ingesting the mixture or attemptinguptake of the mixture using a syringe, because of the ability of theresulting gel to entrap the drug within a consistent, uniform gelmatrix, and due to the ability to resist uptake by or injection from aneedle of a hypodermic syringe because of the thickness and uniformityof the gel matrix.

FIG. 10 provides an image of the gel resulting from the supratherapeuticdose of the comparative 2: 10 dosage forms, suspended in the testmedium. As shown, the gel / test medium mixture was non-uniform, andincluded a concentration of gel material within the upper portion of themedium, indicating that the gel material was not uniformly dispersedwithin the medium. In fact, gel material was absent from a significantvolume of the medium. Also apparent were clumps of gel and portions ofmedium that were clearly visible in the absence of gel material. Theseresults suggest that supratherapeutic doses of the comparative dosageform would provide poor resistance to an attempt to extract drug fromthe supratherapeutic dose by combining it with a solvent and then eitherorally ingesting the mixture or attempting uptake of the mixture using asyringe, because of the likelihood of the presence of regions of themixture of drug and solvent in which gel is absent (i.e., regions inwhich the solvent predominates), and from which drug could be readilyextracted.

Example 8 - Physical Manipulation Studies

Initial Analysis. A single 40 mg tablet of esketamine HCl of Example 3was crushed using a mortar and pestle. The tablet was initiallyfractured by the gentle striking of the pestle, followed by rotation ofthe pestle against the tablet pieces. After visual inspection showedthat no further particle size reduction was possible, the procedure wasterminated. The sample was then collected onto a piece of (pre-tared onan analytical balance) 3 × 3 weigh paper by gently brushing the materialfrom the mortar and weighed. 1000 µm and 500 µm sieves were stackedsequentially and set in a sieve shaker following which, the samples wastransferred from the weigh paper by distributing it across the top sieve(1000 µm). Each sample was sieved for a total of 5 minutes during whichfor the first 60 seconds, the shaker was set to an amplitude of 80 Hz,and for the following 4 minutes, at an amplitude of 50 Hz. Aftersieving, each sieve was carefully removed and the weight of the sieveand manipulated material was recorded. The material from each sieve wasthen transferred into a tarred and labeled collection vessel andweighed. The procedure was repeated in triplicate and the resultsaveraged to show an average manipulation time of 52 seconds, 99.7%weight recovery, 0.2% particle size above 1000 µm and 3.0% particle sizebetween 500 and 1000 µm.

Advanced Analysis. A single 40 mg tablet of esketamine HCl of Example 3was crushed using a mortar and pestle. The tablet was initiallyfractured by the gentle striking of the pestle, followed by rotation ofthe pestle against the tablet pieces for 52 seconds. The sample was thencollected onto a piece of (pre-tared on an analytical balance) 3 x 3weigh paper by gently brushing the material from the mortar and weighed.1000 µm, 500 µm, 212 µm, 106 µm and 75 µm sieves were stackedsequentially and set in a sieve shaker following which, the samples wastransferred from the weigh paper by distributing it across the top sieve(1000 µm). Each sample was sieved for a total of 5 minutes during which,for the first 60 seconds, the shaker was set to an amplitude of 80 Hz,and for the following 4 minutes, at an amplitude of 50 Hz. Aftersieving, each sieve was carefully removed and the weight of the sieveand manipulated material was recorded. The material from each sieve wasthe collected onto a piece of (pre-tared on an analytical balance) 3 × 3weigh paper by gently brushing the material from the sieve and weighed.Sample fractions that resulted in 4% recovery or less were transferredinto 20 mL scintillation vials, fractions that resulted in between 4%and 25% recovery were transferred into 125 mL Erlenmeyer Flasks andfractions that resulted in over 25% recovery were transferred into 250mL Erlenmeyer Flasks. To each vessel with collected material, acalculated prorated volume of 0.1 N HCl (mass recovered on sieve]/[massof manipulated material]*240 mL) was added. The sieve fraction solutionswere then extracted overnight for a minimum of 15 hours at roomtemperature with agitation at 150 RPM following which, aliquots of thesamples were prepared for LC-MS/MS analysis. The procedure was repeatedin triplicate and the results averaged to show an average 98.8% weightrecovery. The results per sieve fraction are shown in Table 20, below.

TABLE 20 Summary of results per sieve fraction Sieve fraction Average%Particle Size Distribution Average% esketamine recovery Average%esketamine uniformity >1000 µm 0.3 0.1 0.8 500 - 1000 µm 5.4 9.7 7.4212 - 500 µm 31.9 62.4 8.0 106 - 212 µm 26.7 18.9 3.0 75 - 106 µm 24.35.2 0.9 <75 µm (pan) 11.4 1.8 0.7

The preceding results demonstrate that the esketamine was notconcentrated in any particular fraction of particle sizes, and in allfractions, the amount of esketamine was less than 10% and the amount ofexcipients greater than 90%. Therefore, physical manipulation is notexpected to allow for the isolation of esketamine by an abuser, and anabuser would likely be required to insufflate the entire 1000 mg ofpowder, including 960 mg of excipients, in order to attempt toadminister the 40 mg of esketamine from any given tablet.

Example 9 - Heat Pretreatment

A series of pretreatments were performed on esketamine HCl tabletsaccording to the present disclosure to evaluate whether heat results ingreater API recoveries when extracted in small volumes of extractionmedia. Crushed 40 mg tablets of esketamine HCl of example 3 were heatedin an oven at various temperatures (200° C. - 300° C.) until they werevisibly browned, visibly charred, or significantly charred. The timerequired to achieve the desired visual outcome was recorded and samplesof the solution’s viscosity was also measured using a Cambridge VL3000viscometer. The samples were then transferred to labeled 20 mlscintillation vials, 20 ml of LC-MS water added and then assayed byLC-MS. The results are shown in Table 21.

TABLE 21 Results of heat pretreatment per visual endpoint Visiblebrowning Visible charring Significant charring Temperature Heatingtime/m:s % esketamine recovery Heating time/m:s % esketamine recoveryHeating time/m:s % esketamine recovery 200° C. 5.00 9.7 12.00 1.3 20.000.0 250° C. 1.40 23.0 2.00 12.0 3.40 7.2 290° C. 1.30 21.0 2.10 7.4 2.320.9 300° C. 1.20 19.2 2.00 9.3 2.20 0.0

Based on this preliminary analysis, samples of material heat treated at250° C. were then transferred into both labeled 20 ml scintillationvials or 60 ml glass sample jars and 20 ml of either water or 0.1 N HCladded. The 20 ml solutions were extracted for 1 hour at room temperaturewith an agitation of 150 RPM and assayed by LC-MS. The 60 ml jars wereextracted overnight and assayed by LC-MS at both 1 and 18 hours. As acomparator, extraction and LC-MS were also performed on non-heat-treatedtablets. The results are shown in Table 22, below:

TABLE 22 Results of% esketamine recovery No treatment Over pre-treatment1 hr extraction 20 ml vial LC-MS water 17.6 13.6 0.1N HCl 32.4 21.7 1 hrextraction 60 ml jar LC-MS water 57.7 28.6 0.1N HCl 57.7 46.2 18 hrextraction 60 ml jar LC-MS water 60.8 41.3 0.1N HCl 61.9 46.2

Direct comparison of verification experiments between oven-heat-treatedand non-heat-treated crushed tablets showed lower average esketamine%recoveries from oven heat pretreated extracts in all cases indicatingthat oven heat pre-treatment of crushed tablets likely would not enhanceAPI recovery.

Example 10 - Simulated In Vitro Nasal Diffusion/Release

A vertical diffusion cell (VDC, or Franz cell) apparatus was used toevaluate the capability of tablets to subside esketamine absorptionacross a membrane simulating nasal diffusion. The VDC used a 33 mmdiameter 12-14 kD dialysis disc as its membrane and the analysis wasperformed using either 46.1 mg pure esketamine HCl powder (40 mg baseequivalent), 161.42 mg/ml esketamine HCl (140 mg/ml esketamine baseequivalent) in pH 4.5 citrate buffer, crushed 40 mg tablets of Example 3or crushed 40 mg tablets of example 3 in 4 ml of pH 4.5 citrate buffer,with the experiments each performed in triplicate. With each VDC in acirculating water bath set at 37° C., phosphate buffer at a pH of 6.4was added to fill each VDC receptor chamber, the membrane slid acrossits rim to seal the chamber, the donor chamber attached and the VDCsealed by a clamp. Stirring of the phosphate buffer at 600 RPM was thenbegun. After equilibration of the apparatus at 37° C. for a minimum of15 minutes, the esketamine was deposited evenly, via the donor chamber,onto the membrane. Apart from the concentrated solution where 200 µl wasdeposited, the equivalent of 40 mg of esketamine base was deposited oneach membrane. At 10, 30 and 60 minutes, 150pl of extract was removedfrom the receiving chamber and replaced by phosphate buffer at a pH of6.4. The extracted aliquots were then assayed for esketamine by LC-MS.The results of the assay are shown in Table 23, below.

TABLE 23 Percentage esketamine recovery 10 minutes 30 minutes 60 minutesEsketamine HCl powder 45.1 75.9 79.2 Concentrated solution 23.3 51.371.8 Crushed tablet 0.7 1.0 2.0 Pre-wet crushed tablet 1.1 2.3 3.3

The results indicate that there is likely no significant esketaminediffusion from crushed tablets across a nasal membrane, in contrast toeither pure esketamine powder or concentrated esketamine solution.

Example 11 - Comparative Stability Testing

Tablet dosage forms according to the present disclosure (20 mg, 40 mg +100 mg esketamine HC1 - see Tables 9, 10, 11, 14 and 15, supra) weretested for stability using HPLC at intervals of 3, 6 and 12 months underaccelerated conditions (40° C. /75% RH) in Brooklyn Part stabilitychambers. Each tablet assayed was prepared according to Example 2 using1 part ethylcellulose in the dry mix to 2 parts in hydroalcoholicsolution. As per Example 2, some of the tablets were prepared usingtablets which were only wet milled (Granumill), and others using tabletswhich were both wet milled (Vector mixer) and then dry milled(Fitzmill).

The assay comprised the use of a Waters Symmetry C₁₈, 100 × 3.0 mm, 3.5µm column at a temperature of 45° C. and a sample temperature of 4° C.,with a mobile phase comprising 0.050% TFA in water and 0.0025% TFA inacetonitrile and UV detection rate of 215 nm.

In addition to known pharmacopeia peaks, a previously unreported peakwas identified which eluted at RRT = 1.29. Table 24 describes theresults of the stability testing over the 12-month period for thisimpurity under accelerated conditions of 40° C. and 75% RH.

TABLE 24 RRT = 1.29 in comparative stability testing of esketamine HCltablets Initial 3 M 6 M 12 M 20 mg tablets of Table 11 (wet milled) NDND 0.09 - 20 mg tablets of Table 11 (wet + dry milled) ND ND ND - 40 mgtablets of Table 10 (wet + dry milled) ND ND ND - 20 mg tablets of Table14 (wet milled) ND ND 0.14 0.18 100 mg tablets of Table 15 (wet milled)ND ND 0.08 -

Example 12 - Stress Testing Studies

Example 12a) Samples of esketamine HCl and various excipients were mixedand stored at 80° C. / 75% RH in a non-acidified diluent. After 4 days,the samples were assayed for the presence of the impurity. The resultsof the assay are described in Table 25.

TABLE 25 Esketamine HCl : excipient stress testing Sample TotalImpurities (%w/w) % RRT=1.3 Esketamine + Placebo Tablets 4.14 DBNQEsketamine + Coated Polymer Granules 5.23 0.079 Esketamine + SiliconDioxide 0.12 ND Esketamine + Carbopol 0.08 ND Esketamine + MagnesiumStearate 0.14 ND Esketamine + MCC 0.46 ND Esketamine + Mannitol 1.30 NDEsketamine + Crospovidone 1.00 ND Esketamine + Sodium Bicarbonate 9.75ND

Example 12b) Samples of esketamine HCl and various excipients were mixedand stored at 80° C. / 75% RH in an acidified diluent. After 7 days, thesamples were assayed for the presence of the impurity. The results ofthe assay are described in Table 26.

TABLE 26 Esketamine HCl : excipient stress testing Sample % RRT=1.3Esketamine + Ethyl Cellulose ND Esketamine + E100 0.143 Esketamine +Compritol ND Esketamine + Hypermellose ND Esketamine + Uncoated PolymerGranules ND

Example 12c) 4, 16 and 32% coated esketamine HCl granules were preparedaccording to Example 2 and stored at 80° C. / 75% RH. After 7 days, thesamples were assayed for the presence of the impurity. The results ofthe assay are described in Table 27.

TABLE 27 Coated esketamine HCl granules stress testing Esketamine HClcoating Eudragit E100:Esketamine HCl % RRT=1.3 4% 2.61 1.58 16% 0.650.60 32% 0.32 0.30

Example 13 - Isolation and Identification of Impurity

1 g of esketamine and 5 g of Eudragit-E100 were dissolved together inabout 70 mL of 0.1 N HCl. The sample was then heated at 90° C. for 10days. Samples for analysis were prepared by extracting 1 mL of thedegraded solution at various time points and diluting these samples with13 mL 0.1 N HCl.

Samples extracted at both 6 and 10 days were identified by HPLC,according to the methods described in Example 11, to contain theimpurity eluting at RRT = 1.29.

Using preparative MPLC, the solutions were separated over severalinjections by an ISCO Redisep Gold, HP C18 100 g Column, with aninjection of 5 mL and a flow rate of 60 mL/min, mobile phase of 0.1% FAin Water and 0.1% FA in acetonitrile, UV detection of 215 and 270 nm.The fractions containing the RRT = 1.29 impurity were tracked by HPLC,combined, and concentrated by rotary evaporation to remove acetonitrile.By this initial isolate, the impurity was found to be approximately 50%pure and the concentrate (-400 mL) was stored at -20° C. for secondaryconcentration and isolation.

A second attempt at concentrating and isolating the impurity wasperformed by loading the concentrate (-400 mL) above onto a RediSep 100g High Performance GOLD, C18 column. After loading, the desired impuritywas eluted from the column using the gradient conditions previouslydescribed. The RRT = 1.29 impurity fractions were again combined andconcentrated by rotary evaporation using preparative MPLC using the sameconditions previously described. Two fractions were found which showedthe RRT = 1.29 impurity, one at -90% purity and a second at -95% purity.Both fractions were concentrated separately by rotary evaporation toremove acetonitrile. The ~90% pure sample was stored at -20° C. whilethe -95% pure sample was loaded on a 30 mg Waters HLB SPE cartridgeprepared by washing it with ~10 mL of acetonitrile and ~10 mL water. Thesample was washed with 2 mL of water and eluted with 2×2 mL of 60%acetonitrile. No significant amount of the RRT = 1.29 impurity wasdetected in any solution apart from the first 60% acetonitrile elutionfraction. This fraction was then frozen and lyophilized to give thefinal isolate of 0.12 mg and 95.7% purity. NMR analysis of the isolateidentified the impurity to be2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one.

What is claimed:
 1. An immediate release tablet comprising between 20 mgand 100 mg of esketamine (base equivalent); and a pH adjuster in anamount of no more than about 2 wt%; wherein the tablet contains no morethan 5 wt% of2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one, asmeasured by HPLC, after storage at 40° C. ± 2° C. and 75% ± 5% relativehumidity for six months.
 2. The immediate release tablet of claim 1,comprising 40-60 mg of esketamine (base equivalent).
 3. The immediaterelease tablet of claim 1, comprising 40 mg of esketamine (baseequivalent).
 4. The immediate release tablet of claim 1, comprising 60mg of esketamine (base equivalent).
 5. The immediate release tablet ofclaim 1, wherein the tablet is a product of a wet milled process or drymilled process.
 6. The immediate release tablet of claim 1, wherein thetablet is a product of a dry milled process.
 7. The immediate releasetablet of claim 1, comprising2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one in anamount of no more than 0.2 wt% after storage at 40° C. ± 2° C. and 75% ±5% relative humidity for six months.
 8. The immediate release tablet ofclaim 1, comprising a non-detectable amount of2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one, asmeasured by HPLC, after storage at 40° C. ± 2° C. and 75% ± 5% relativehumidity for six months.
 9. The immediate release tablet of claim 1,wherein the tablet is abuse resistant.
 10. A method of treatingdepression in a human subject in need thereof comprising administeringto the subject an immediate release tablet of claim
 1. 11. A method ofmanufacturing an immediate release tablet according to claim 1,comprising dry milling esketamine and a pharmaceutically acceptableexcipient.
 12. A method comprising preparing an immediate release tabletcomprising between 20 mg and 100 mg of esketamine (base equivalent);exposing the tablet to a storage period of six months; after the storageperiod, determining by HPLC that the total amount of2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one presentin the tablet is no more than about 5 wt%.
 13. The method of claim 12,wherein the tablet is exposed to 40° C. ± 2° C. and 75% ± 5% relativehumidity.
 14. The method of claim 12, wherein the tablet comprises 40-60mg of esketamine (base equivalent).
 15. The method of claim 12, whereinthe tablet comprises 60 mg of esketamine (base equivalent).
 16. Themethod of claim 12, wherein the tablet comprises a pH adjuster.
 17. Themethod of claim 16, wherein the tablet comprises 2 wt%, based on theweight of the tablet, of the pH adjuster.
 18. The method of claim 12,wherein the2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one ismeasured in an amount of no more than 0.2 wt% after the storage period.19. The method of claim 12, wherein the2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one ismeasured in a non-detectable amount after the storage period.
 20. Theimmediate release tablet prepared according to the method of claim 12.